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Managing Pancreatic Lesions in VHL Syndrome
Indiana University HealthVHL Alliance Annual Family Meeting
19 October 2019
Department of Surgery Indiana University School of Medicine
Michael G. House, MD, FACSAssociate Professor
Chief, Division of Surgical OncologyDirector, IU Pancreatic
Cancer Program
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Disclosures
I have no professional conflicts of interest with regards to the
content of this lecture.
It’s easy to hurt a patient with VHL syndrome with bad decision
making.
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Overview
I. Natural history of PNETs and pancreatic cysts
I. Patients live a long time in the absence of treatment-related
morbidity
II. PNETs in patients with syndromes
I. MEN1, VHL, NFIII. Differential diagnosis
I. Appearance and clinical findings
IV. Non-functional PNETs have heterogeneous behavior
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VHL Syndrome
Autosomal dominant inherited syndrome caused by mutations of
VHL
Incidence 1:36,000Penetrance 90% by age 65 yrsClinical
manifestations:
CNS hemangioblastomasRCCRetinal angiomasPheochromocytoma
PNETsOthers: panc cysts, renal cysts, epididymis cysts
Machens et al. Clin Endocrinology 2007. 67:613-22.
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Pancreatic cysts in VHL
Frequent finding
Cysts are present in 70+% of patients
Two types of cysts
Simple cyst (common) and
Serous cystadenoma (uncommon)
Complications of pancreatic cysts (rare)
Bile duct obstruction
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Pancreatic cysts in VHL
10 10 1 1 X:1:1:Body:Body
S:1.50:1.50:PFP\FSPFP\FS:1:1345345
Z:1.6Z:1.6
LOC:-31.1LOC:-31.1THK:2.60 --THK:2.60 --
HFHF
VHL-associated pancreatic cysts:• Usually small• Can be found
throughout the pancreas• May enlarge to cause symptoms (pain,
duct obstruction)• Do not cause dysfunction of the
pancreas (e.g. diabetes, EPI)
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Endocrine Tumors of the Pancreas
central
peripheral
Islets of Langerhans•2% of the total pancreatic mass•Receive 20%
of the pancreatic blood supply
Alpha cellsGlucagon, 20% of islet cells, body and tail
Beta cellsInsulin, 75% of islet cells, evenly distributed
Delta cellsSomatostatin, 5% of islet cells, head
PP cellsPancreatic polypeptide, 5% of islet cells, head
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VHL Syndrome: Clinical Presentation of Pancreatic Neuroendocrine
Tumors (PNETs)
Non-functional PNETs (>75%)Asymptomatic
Functional PNETs (20%)Gastrinoma (50%)
Zollinger-Ellison SyndromeInsulinoma (20%)
Hypoglycemic or Neuroglycopenic SyndromeVIPoma (5%)
WDHA SyndromeGlucagonoma (2%)
Metz and Jensen. Gastroenterology 2008. 135:1469-95.
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Non-functional PNETsLarge size if clinical symptoms present
Obstruction (stomach, duodenum, CBD, colon), pain, or bleeding,
jaundice
*Incidental finding
HypervascularCT findings: cystic changes, calcification
Approx ½ of tumors LN+ and/or liver mets
Histology: neuroendocrine phenotype, synaptophysin and
chromogranin IHC+
Treatments:
Resection (or ablation) primary
*Observation
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Non-functional PNETs Location
Lairmore et al. Ann Surg 2000. 231:909-18.
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PNETs Detection: Cross-sectional Imaging
Advantages:
•Convenient•Sensitive•Operative planning•Reasonable cost
Disadvantages:
•Misses smaller tumors (i.e. < 1 cm)
•No duodenal evaluation•Misses small volume metastases
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PNETs: Detection by EUS
Advantages:
•Very sensitive•Non-invasive•Evaluate duodenum
Disadvantages:
•Operator dependent•Costly•Incidental findings >>
Increased chance for patient harm
Gastrinoma Triangle
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B B 258 258me: 710me: 710
93 93 31 31
Brillia Brillia
9/16/2015 9:19 9/16/2015 9:19 IM Time 9:19 IM Time 9:19
------Acq No: 1Acq No: 1KVp: 120KVp: 120Kernel: BKernel: BmAS:
283mAS: 283ExpTime: 711ExpTime: 711mA: 398mA: 398Tilt: 0Tilt: 0RD:
331RD: 331
9/16/2015 9:19:56 IM Time 9:19:58 IM Time 9:19:58
IodIodLOC: 138LOC: 138
TH THK
Compressed 1Compressed 1
DFOV:33.1x33.1DFOV:33.1x33.1W: 3W: 3C: C:
Z Z
RR
DOTA-NOC or -TATE ImagingDOTANOC - PET68Ga-DOTA,
1-Nal-OctreotateHigh affinity for SST receptors 2, 3, 5
*Insulinoma low SST expression for types 2 and 5, high SST 3
expression
NF-PNETs, gastrinoma, VIPoma, carcinoids high SST 2 and 5
expression
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Imaging for Localization and Staging
Imaging Modality Primary Tumor Liver Metastasis Extrahepatic and
Liver TumorsEUS 95% 46% 29%
CT 31% 42% 38%MRI 30% 71% 45%Angio 28% 62% 40%SRS 58% 92%
70%
DOTA-NOC 85% 93% 95%
Gibril F et al. Ann Intern Med. 1996 Jul 1;125(1):26-34.
NIHVinik AI. Endocr Pract 2014; 20(11):1222-30.
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Incidental PNET
42 yo woman with hereditary VHL syndrome
CT reveals a 15 mm solid and cystic lesion in the tail
EUS + FNA: PNETs w cystic features, 14 mm , Ki67
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2017
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Factors Influencing Malignancy: Does Size Matter?
Lairmore et al. Ann Surg 2000. 231:909-18.
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Non-functional PNETs are Heterogeneous
Kann et al. Endo-related Ca 2006. 13:1195-2012.
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Pancreatic Neuroendocrine Tumors: WHO Classification (2017)
Grade Differentiation KI-67 Index (%) Mitotic count/10 HPF
G1 (low) well < 2 20 >20
FNA, CNB CNB
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Jensen RT. Ann Oncol. 1999;10(Suppl 4)2Raj et al. Pancreas 2017;
46:758-63.
Factors associated with poor prognosisLiver metastasisExtent of
liver metastasisLymph node metastasis
Extrahepatic metastasis
Development of paraneoplastic syndromeExcessive hormone
hypersecretion
Histologic grade? Intact MGMT expression2
Prognostic factors for PNETs
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Extent of Disease
Median Survival
5 year Overall
10 Year Overall
Local > 10 yrs 85% 70%
Regional 9.3 yrs 70% 55%
Distant 2.3 yrs 30% 20%
Evans DB. Cancer, Principles and Practice of Oncology. 2015;
1205-17.
Overall Survival for Resected PNETs by Stage
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VHL: Non-functional PNETsUsually asymptomatic
(surveillance)Usually multifocalEven distribution thru
pancreasConcomitant with functional PNETsVariable biology
Size, mitotic rate, proliferative indexSpecific VHL mutations,
type 1/2
When should these tumors be removed? With what operation?
Kouvaraki et al. World J Surg 2006; 30(5): 643-53.
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Interventions for PNETs
• High-risk/grade tumors– Pancreatoduodenectomy– Left
pancreatectomy + splenectomy
• Low-risk/grade tumors– Enucleation– Central pancreatectomy–
Spleen-preserving left pancreatectomy
SURGICAL
NON-SURGICAL
• EUS-guided ablation• Radiotherapy• PRRT
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What should be done with small
nonfunctional pancreatic
neuroendocrine tumors?
Observe or Resect?
Pancreatic Neuroendocrine Tumors
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N=20
N=13
N=10
N=116
Nonfunctional PNETs < 2 cm: Resect v Observe
Sharpe SM, Baker MS. JOGS 2015; 19:117-23
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Overall Survival of Nonsurgical Management vs. Surgical
Resection of Pancreatic Neuroendocrine tumors (< 2 cm)
Finkelstein et al. J Gastrointest Surg 21:855-866, 2017
Meta-analysis11 studies (2 prospective)
Surgical (N=1491), Nonsurgical (N=1607)
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Treatment Toxicity for Non-Functional PNETs
Swanson RS. Ann Surg Onc 2014. 21:4059-67.
Hospital Case Volume
Mor
talit
y %
Chart1
< 5< 5
5-95-9
10-3910-39
>40>40
30 day
90 day
7.5
12.5
4.7
9
3
6.4
1.6
4.4
Sheet1
30 day90 day
< 5813
5-959
10-3936
>4024
To update the chart, enter data into this table. The data is
automatically saved in the chart.
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Metastatic PNETsResection and Directed Therapies
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Metastatic PNETsResection and Directed Therapies
Survival after liver resection* Outcomes after liver
resection*
*House et al. J GI Surg 2006. 10:138-45.Sarmiento et al. JACS
2003. 197:29-37.Norton et al. Surg 2003. 134:1057-63.
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Chemotherapy for PNETsMulti-center randomized trial of 105
patients with
unresectable metastatic neuroendocrine carcinoma
• Streptozocin plus doxorubicin superior to streptozocin plus
fluorouracil
Moertel CG et al. N Engl J Med. 1992 Feb 20;326(8):519-23.
STZ/5-FU STZ/doxorubicinTumor regression* 45% 69%Time to tumor
progression* 6.9 months 20 months
Median survival* 1.4 years 2.2 years*p < 0.05
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PNET: Targeted Therapy
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Radiation TherapySomatostatin receptor radionuclide therapy
(SRRT)
RJ Hicks. Ca Imaging 2010.
Tumor response to [(177)Lu] DOTA-Octreotate in patients with
neuroendocrine tumors
50-100% reduction 39%
25-50% reduction 6%
No change 44%
Tumor progression 11%
• Somatostatin receptor (+) tumors• The toxicity was generally
mild bone
marrow toxicity
LuTate Therapy
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VHL Pancreatic Neuroendocrine TumorsRecommendations for
Follow-up Surveillance
Q 1 yearPhysical examBiochemical markers
(Chromo A)
Plus one of the following:EUSMRICT abdomen DOTA-TATE –
SPECT*
*only for malignant PENs
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TAKE HOME MESSAGEPancreatic endocrine tumors (PNETs) occur in
10% of patients with VHL Syndrome
Clinical and biochemical diagnosis
Imaging for localization and staging
Resection when technically possible (even for stage IV)
Treatment sequencing recommendations are unclear
Palliation: debulking, ablation, liver embolization, Octreotide,
chemotherapy, PRRT (Lutathera)
Slide Number 1DisclosuresOverviewVHL SyndromePancreatic cysts in
VHLPancreatic cysts in VHLSlide Number 7VHL Syndrome: �Clinical
Presentation of Pancreatic Neuroendocrine Tumors (PNETs)Slide
Number 9Slide Number 10Slide Number 11Slide Number 12Slide Number
13Imaging for Localization and StagingSlide Number 15Slide Number
16Slide Number 17Slide Number 18Pancreatic Neuroendocrine Tumors:
WHO Classification (2017)Slide Number 20Slide Number 21Slide Number
22Interventions for PNETsSlide Number 24Slide Number 25Overall
Survival of Nonsurgical Management vs. Surgical Resection of
Pancreatic Neuroendocrine tumors (< 2 cm)Slide Number 27Slide
Number 28Slide Number 29Chemotherapy for PNETsSlide Number
31Radiation TherapySlide Number 33Slide Number 34