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

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.

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

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.

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

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)

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

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.

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

Non-functional PNETs Location

Lairmore et al. Ann Surg 2000. 231:909-18.

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

PNETs: Detection by EUS

Advantages:

•Very sensitive•Non-invasive•Evaluate duodenum

Disadvantages:

•Operator dependent•Costly•Incidental findings >> Increased chance for patient harm

Gastrinoma Triangle

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

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.

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

2017

Factors Influencing Malignancy: Does Size Matter?

Lairmore et al. Ann Surg 2000. 231:909-18.

Non-functional PNETs are Heterogeneous

Kann et al. Endo-related Ca 2006. 13:1195-2012.

Pancreatic Neuroendocrine Tumors: WHO Classification (2017)

Grade Differentiation KI-67 Index (%) Mitotic count/10 HPF

G1 (low) well < 2 20 >20

FNA, CNB CNB

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

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

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.

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

What should be done with small

nonfunctional pancreatic

neuroendocrine tumors?

Observe or Resect?

Pancreatic Neuroendocrine Tumors

N=20

N=13

N=10

N=116

Nonfunctional PNETs < 2 cm: Resect v Observe

Sharpe SM, Baker MS. JOGS 2015; 19:117-23

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)

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.

Metastatic PNETsResection and Directed Therapies

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.

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

PNET: Targeted Therapy

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

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

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