Pancreatic Cysts Saltzman ACG St Louis 2013s3.gi.org/wp-content/uploads/2013/08/13ACG_Midwest...1-2...

John R. Saltzman, MD, FACG

Cystic lesions of the pancreas: When are they malignant?

John R Saltzman MD, FACG, FASGE

Director of EndoscopyDirector of Endoscopy

Brigham and Women’s Hospital

Associate Professor of Medicine

Harvard Medical School

Objectives

• Know the differential diagnosis• Know the differential diagnosis

• Be familiar with each clinical entity

• Understand the role of EUS and FNA

• Use the most recent algorithms to optimally manage pancreatic cystsoptimally manage pancreatic cysts

ACG Regional Postgraduate Course - St. Louis, MO Copyright 2013 American College of Gastroenterology

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Pancreatic cancer

• Pancreatic cancer is the 4th leading cause of cancer death in United States

• 45,220 Americans will be diagnosed in 2013• The average life expectancy with metastatic

disease is 3-6 months

• Pancreatic cancer has the highest mortality• Pancreatic cancer has the highest mortality rate of all major cancers

• 1.2% individual risk

Siegel R. CA Cancer J Clin. 2013 Jan;63(1):11-30

Pancreatic cancer development

ColonAdenoma-Carcinoma Sequence:Sequence:

Intervention bypolypectomy

PancreaticPanIN-CarcinomaSequence:

Potential for Intervention


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Pancreatic tumors

CysticMalignant Solid

S lid

Adenocarcinoma Intraductal papillary mucinous neoplasm (IPMN)

Benign C tiSolid

Neuroendocrine Serous Cystadenoma

Benign Cystic

Prevalence of pancreatic cystic lesions

• 2,832 CT scans

• Incidental cysts 2 – 38 mm

• Prevalence of cysts: 2.6%

• Age risk factor

• Prevalence >70 years): 3mm incidental pancreatic cystPrevalence >70 years):

– 10% (mostly side-branch IPMN)

Laffan TA. Am J Roentgenol. 2008;191(3):802-7.

3mm incidental pancreatic cyst

Cancer in situ (2.4%)De Jong K. Pancreas 2012;41:278-282.


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Differential diagnosis of pancreatic cysts

– Benign Pseudocystsy Serous cystadenoma Intraductal papillary mucinous neoplasms (IPMN)

(branch type)—small (<3 cm) and no associated mass

– Potential to turn into Cancer Mucinous cystadenoma/cystic neoplasm IPMN (main duct) IPMN (branch duct)—large (>3 cm) and/or mass Solid pseudopapillary neoplasm (SPN)

– Cancer Adenocarcinoma Neuroendocrine tumor

Pseudocyst/walled-off pancreatic necrosis

No epithelial lining

Contains pancreatic secretions, necrotic debris or blood

Thin or thick wall

Solitary, unilocular or septated

Cyst fluid cola colored


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Pseudocyst cytology and fluid

• Inflammatory cells in wallInflammatory cells in wall• Pigment-laden macrophages• Cyst fluid

– High amylase– No mucin– Low CEA– No DNA

Brugge W. Curr Opin Gastroenterol 2004;20:488

Serous cystadenoma

Cuboidal epithelial cells with glycogen

Female > males (3:1) 5th to 7th decade Anywhere in pancreas Central stellate scar 30% 70-90% microcystic or

honeycomb appearance (>6 cysts <3mm)

>50% incidental finding Benign, slow growing


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Serous cystadenoma cytology and fluid

• Fluid thin, often bloodyFluid thin, often bloody• Fluid analysis: CEA<5, low amylase• Few mutations; no kRAS• Small cysts grow 1 mm per year

Belsley NA. Cancer. 2008 Apr 25;114(2):102-10.

Mucinous cystic neoplasm

> 95% female

Mean age 45

>95% body/ tail

Peripheral calcium

Single cyst, incidental

Mucin-secretingMucin secreting epithelial cells

Ovarian-like stroma

Malignant potential


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Mucinous cystadenoma cytology and fluid

• Viscous mucoid fluid

CEA staining

• CEA>200, low amylase• Kras mutations:

– sensitivity 45%– Specificity 96%

• Malignant >4 cm usually

Intraductal papillary mucinous neoplasms (IPMN)

Proliferation of m cino s cells of• Proliferation of mucinous cells of pancreatic duct

• Cystic dilations of ductal system with overproduction of mucus

• Can affect main duct side (branch)Can affect main duct, side (branch) ducts or both

• Symptoms: abdominal pain, pancreatitis, jaundice, diabetes or none


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Types of IPMN

Main duct

Main duct type IPMN

Branch duct

Michaels PJ. Cancer 2006 Mar; 20-5

Branch duct type IPMN

IPMN characteristics• Mucin-producing cells in

papillary patterns t d t d tconnected to duct

• Localized, multifocal, entire duct

• Head 60%, body/tail 40%, older males

• Branched duct90% often incidental• 90%, often incidental

• 30-40% multifocal • 5-15% cancer

• Main duct• 10% of IPMN’s• 63% cancer in 5 years


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IAP consensus IPMN guidelines

R d i l i 1 fRecommend surgical resection ≥ 1 feature:• Symptoms i.e. obstructive jaundice

• Main pancreatic duct ≥ 1 cm

• Intramural nodule/ solid component

• Cyst cytology suspicious or positive for cancerCyst cytology suspicious or positive for cancer

• Cyst ≥ 3 cm (worrisome, but not by itself)

Tanaka M. Pancreatology 2006;6(1-2):17-32;Tanno S. Gut 2008;57:339-343.


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YesEUS: Mural nodulesDil t d i d t

Size <1 cm Size 1-3 cm Size >3 cm

Monitoring of branch duct IPMN lesions

MRI /CT in 2-3 years

No

MR or CT

1-2 cm every year x 2

YesDilated main ductMalignant cytologyAbrupt change in PD

1-2 cm every year x 2

2-3 cm, EUS in 3 months than alternate EUS/MRI

Stable lesion without nodules

Symptomatic, young/fit or

High-risk stigmata Resect

Tanaka M. Pancreatology 2012;6(1-2):17-32

Young/fit or high risk stigmata

Yes

No

Solid pseudopapillary neoplasm (SPN)

• Least common of pancreatic cystic neoplasms (<4% resected)

• Also called papillary cystic tumor of the pancreas and papillary cystic neoplasm

• Occurs in young (30’s) women (>90%)

• Commonly in body and tail

• Malignant potential (15%)

• Surgical removal is curative


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Cystic neuroendocrine tumors

• 8% resected pancreatic cystic neoplasms

M t t ti f d i id t ll• Most asymptomatic found incidentally

• Occurs in men and women

• Typical age 60-70 years

• Low CEA, high yield of EUS cytology

• Cystic lesion with hypervascular rim or solid component

• Malignant potential

• Surgical removal is curative

Malignant cystic neoplasms

• All malignant cysts arise from mucinous lesions

• Associated mass• CEA > 1000, low amylase• LOH (kras + mutation):

– Sensitivity 37% – specificity 96%

• Malignant cytologySahani DV. Clin Gastroenterol Hepatol. 2008 Nov 13


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Radiology of pancreatic cysts

Accuracy Sensitivity SpecificityAccuracy Sensitivity Specificity

CT and MRI (58) benign vs. malignant

76-91% - -

CT and MRI correct diagnosis

43-67% - -

CT premalig/malignant 78% 75% 80%p g gvs. benign (100)

CT mucinous vs. other 75% 59-71% 77-85%

Leading diagnosis by radiologist correct 43-55%

EUS of pancreatic cysts

Accuracy Sensitivity Specificity

Mucinous vs. non-mucinous

51% 56% 45%

Neoplastic 75% - -

Non-neoplastic 50% - -

Ahmad et al. GIE 2003;58:59.


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Sensitivity and specificity curves for cyst fluid CEA for diagnosing mucinous cystic lesions

Brugge WR. Gastro 2004;126:1330-1336

Differentiating between mucinous and non-mucinous lesions

EUS Cytology CEA(C t ff 192)

y gy(Cut-off 192)

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 < 0.001Brugge WR. Gastroenterology. 2004 May;126(5):1330-6


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Tumor suppressor gene mutations

p53 at 17p13.1 mutated

p53 and associated STR allelesdeleted

STR* markers

p53 p53 p53

p53 at 17p13.1 mutated

p53 and associated STR allelesdeleted

STR* markers

p53 p53 p53

STEP 1 STEP 2STEP 1 STEP 2

*STR: Short Tandem Repeat sequences (microsatellites)

STEP 1

Pro-oncogenic

STEP 2

Loss of

(Allelic Imbalance)

STEP 1

Point Mutation

STEP 2

Loss of Hetereozygosity

Pancreatic cyst DNA analysis (PANDA) study

• 113 patients with pancreatic cysts who underwent surgery– 40 malignant40 malignant– 48 premalignant– 25 benign cysts

• Cyst fluid k-ras mutation in the diagnosis of mucinous cysts– Odds ratio 20.9– Sensitivity 45% and specificity 96%

• Components of DNA analysis detecting malignant cysts– Allelic loss amplitude over 82% (AUC 0.9)Allelic loss amplitude over 82% (AUC 0.9)– High DNA amount (optical density ratio >10, AUC 0.79)

All malignant cysts with negative cytologic evaluation (10/40) diagnosed as malignant by using DNA analysis

Khalid A. Gastrointest Endosc. 2009 May;69(6):1095-102


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Dilemma of pancreatic cysts• Common – 3-10% of abdominal CT have incidental

pancreatic cysts• Most small (<3 cm) pancreatic cysts are benign• Most small (<3 cm) pancreatic cysts are benign

branch-duct IPMN• Cyst sampling tests for mucinous lesions; however

– Neither cytology nor fluid CEA is perfect in deciding mucinous versus non-mucinous

– Natural history of mucinous cystadenomas is unknown– Branch-duct IPMN are mucinous but have low malignant

potential

• Only treatment is surgical resection– Real morbidity with surgery– Who benefits from surgery?

American College of Gastroenterology guidelines

• CT scanning best initial test (3-phase MDCT)

• Use EUS for diagnostic uncertainty with selective FNA depending on clinical setting

• Monitor indolent < 3 cm BD-IPMNs

• Cyst fluid analysis : CEA most important

• Use cytology in high risk lesions

• Surgical resection for MCN, main duct IPMN and BD-IPMN at high risk for malignancy

Khalid A, Brugge W. Am J Gastroenterol. 2007 Oct;102(10):2339-49


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