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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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John R. Saltzman, MD, FACG
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
ACG Regional Postgraduate Course - St. Louis, MO Copyright 2013 American College of Gastroenterology
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John R. Saltzman, MD, FACG
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.
ACG Regional Postgraduate Course - St. Louis, MO Copyright 2013 American College of Gastroenterology
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John R. Saltzman, MD, FACG
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
ACG Regional Postgraduate Course - St. Louis, MO Copyright 2013 American College of Gastroenterology
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John R. Saltzman, MD, FACG
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
ACG Regional Postgraduate Course - St. Louis, MO Copyright 2013 American College of Gastroenterology
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John R. Saltzman, MD, FACG
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
ACG Regional Postgraduate Course - St. Louis, MO Copyright 2013 American College of Gastroenterology
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John R. Saltzman, MD, FACG
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
ACG Regional Postgraduate Course - St. Louis, MO Copyright 2013 American College of Gastroenterology
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John R. Saltzman, MD, FACG
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
ACG Regional Postgraduate Course - St. Louis, MO Copyright 2013 American College of Gastroenterology
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John R. Saltzman, MD, FACG
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.
ACG Regional Postgraduate Course - St. Louis, MO Copyright 2013 American College of Gastroenterology
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John R. Saltzman, MD, FACG
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
ACG Regional Postgraduate Course - St. Louis, MO Copyright 2013 American College of Gastroenterology
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John R. Saltzman, MD, FACG
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
ACG Regional Postgraduate Course - St. Louis, MO Copyright 2013 American College of Gastroenterology
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John R. Saltzman, MD, FACG
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.
ACG Regional Postgraduate Course - St. Louis, MO Copyright 2013 American College of Gastroenterology
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John R. Saltzman, MD, FACG
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
ACG Regional Postgraduate Course - St. Louis, MO Copyright 2013 American College of Gastroenterology
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John R. Saltzman, MD, FACG
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
ACG Regional Postgraduate Course - St. Louis, MO Copyright 2013 American College of Gastroenterology
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John R. Saltzman, MD, FACG
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
ACG Regional Postgraduate Course - St. Louis, MO Copyright 2013 American College of Gastroenterology
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