NEUROENDOCRINE TUMORS OF PANCREAS

DR SUHAS KR

Definition of NETS:• Neuroendocrine tumors (NETs) - neoplasms that arise from cells

of the endocrine (hormonal) and nervous systems. • Share common features, similar microscopic features , having

special secretory granules, and often producing biogenic amines and polypeptide hormones.

• Arise from various neuroendocrine cells whose normal function is to serve at the neuroendocrine interface. Neuroendocrine cells present not only in endocrine glands throughout the body that produce hormones, but also diffusely in all body tissues

• NETs show amine precursor (L-DOPA and 5-hydroxytryptophan) uptake and decarboxylation to produce biogenic amines such as catecholamines and serotonin.

Characteristics of Neuroendocrine

Tumors• Rare• Usually small, <1 cm• Slow growing, months to years, “cancer in slow motion”• Usually metastasize before becoming symptomatic,

often when tumor is <2 cm• Expression is episodic, may be silent for years• Symptoms mimic commonplace conditions and often

are misdiagnosed

Introduction • Incidence : 1-10/million• Age : 30-60years• pNETs comprise 1-2% of all pancreatic tumors and

7% of NETs in general,• For all PNENs, the 5- and 10-year survival rates

are about 65% and 45%, respectively

Origin

Syndromic pNETS• 10% are associated with an underlying genetic

syndrome(MEN1) and type IV (MEN4) –pNETS in 80-100% of patients • Small, multifocal and microscopic• Gastrinomas (>80% duodenal) develop in 54% of

MEN-1 patients, insulinomas in 18% and glucagonomas, VIPomas, GRFomas, somatostatinomas in <5%

• Von Hippel-Lindau disease (VHL),-10% patients develop pNETS , 98% of all the PNETs are NF-PNETs

• Neurofibromatosis type I (NF1), tuberous sclerosis complex (TSC)

Classifications

Grading

ENETS STAGING

Classification • functional versus non-functional• non-functional if the patient does not suffer from

symptoms due to hormone hyper-secretion, even if hormone levels are elevated on laboratory evaluation.

• 90% - non-functional.• the treatment of these tumors follow the same general

principles but the distinction is sometimes important for clinical presentation, diagnosis of these tumors.

Nonfunctioning Pancreatic endocrine tumors (NF-PNETS)• NF-PNETS are intrapancreatic in location,

characteristically large (70% >5cm)• 60-85% having liver metastases in most series• abdominal pain (40-60%), weight loss, or jaundice • Even at an advanced stage, the tumors are slow

to progress, with rates of 5-year survival in advanced disease estimated at 30–50%

Biochemical Assessment and Monitoring for PNETSChromogranin A (CgA) and Chromogranin B (CgB): • CgA can be used as a marker in patients with both functional

and non-functional pancreatic endocrine tumors • false positive - decreased renal function and treatment with

proton pump inhibitors and even essential hypertension • sensitivity varies from 77.8 to 84% and specificity from 71.3

to 85.3% • blood levels depend upon tumor mass, burden or progression

and malignant nature of the tumor

Biochemical markers • Pancreatic Polypeptide (PP) - PP sensitivity - 54% in

functioning tumors, 57% in non-functioning, 63% in pancreatic tumors

• Neuron-Specific Enolase (NSE): high sensitivity (100%),very low specificity (32.9%) - thyroid and prostatic carcinomas, neuroblastomas, small-cell lung carcinoma, carcinoids, GEP NETs and pheochromocytomas

Imaging Conventional imaging studies for PNETs studies (CT, MRI, ultrasound, angiography)

>70% of PNETs>3 cm, they detect <50% of most PNETs<1 cmSomatostatin receptor scintigraphy (SRS) - 111Indium-DTPA-octreotide (octreoscan) frequently (>80%, except insulinomas) over-express somatostatin receptors (particularly subtypes sst 2, 5)50-70% of primary PNETS and >90% of patients with metastatic disease

Endoscopic ultrasound (EUS)EUS combined with fine needle aspirationlocalizing intrapancreatic PNETs than extrapancreatic PNETs (e g insulinomas) - > 90% sensitivity • MEN 1 syndrome Functional localization (assessing hormonal gradients) • rarely used except in occasional patients with

insulinomas or gastrinomas not localized by other imaging methods

ROLE OF PET • Those related to receptor expression and those

reflecting tumor metabolism • SSAs labeled with the positron emitter 68Ga and the

most often used preparations are 68Ga-DOTATOC, 68Ga-DOTANOC and 68Ga-DOTATATE.

• The use of PET scanning in undifferentiated tumors is highly effective.

• The role in well-differentiated NETs is less delineated. Only tumors with high proliferative activity and dedifferentiation show FDG-PET uptake

Investigation algorithm

ENETS Consensus Guidelines5 OH tryptophan scan - new imaging method with better senstivity

Insulinoma• Most common 60%• Origin- β cells almost universally within the pancreas (1/3head – 1/3 body – 1/3 tail)• F>M• 90% benign, 10% malignant• Most solitary, 10% multiple • 21% MEN 1 – insulinomas• The median age at diagnosis- 47yrs

Clinical Presentation• Whipple’s triad - (1) symptoms of hypoglycemia, (2)

plasma glucose level <2.2 mmol/l ( <40 mg/dl), and (3) relief of symptoms with administration of glucose.

Weight gain Diagnosis: -72hrs fasting test

Neuroglycopenic symptoms Serum glucose<45mg/dl Serum level of insulin >5μU/L Serum C-peptide(>0.7ng.ml),Proinsulin >6.5

pmol

Invasive• Selective angiography• EUS – 77%, EUS guided FNA• Portal Venous sampling-80%• Calcium angiogram-90%• IOUS-90%

ManagementPreoperative managementOptimization of hypoglycemia - slowly absorbable forms of carbohydrates (e.g. starches, bread, potatoes, rice) generally are preferred.

• Diazoxide and Natriuretic Benzothiadiazines•  150 to 450 mg/d in combination with trichlormethiazide in

doses of 2 to 8 mg/d• Other options - CCB s, propranolol, dilantin, corticosteroids

Gastrinoma /Zollinger-Ellison Syndrome• Second most frequent• 1-2 / million• 60% malignant• 75 % sporadic• M>F• Average age -50 years,5 to 10 years earlier in

MEN-1• 25 % MEN-1

Oberg K, Eriksson B. Endocrine tumours of the pancreas. Best Pract Res Clin Gastroenterol

2005;19:753–81.

ZES contd.• Clinical Features

– Abdominal Pain 70%– Diarrhea 70%– Heartburn 50%– Nausea 25%– Vomiting 20%– Weight Loss 15%

Fasting Serum Gastrin (Cessation of PPI for 1 week) > 150pg/ml

Basic acid output >  15 mmol/h

Provocative test(Secretin stimulation test) -Rise by 200 pg/mL or more

Pre op antisecretory agents - PPI

VIPOMA(Verner-Morrison Syndrome)

• 0.05-0.2 new cases per million adults • Third most common neuroendocrine tumor of

the pancreas• Solitary, found in body or tail.• 2/3 malignant• Male-to-female ratio in children - 1:1, in adults. - 1:3

Clinical features • Constant features

o Watery Diarrhea o Hypovolemia o Hypokalemiao AcidosisWDHA SYNDROME

• Variable featureso Achlorhydria or

hypochlorhydriao Hypercalcemiao Hyperglycemiao Flushing with rash.

VIPoma contd.• Diagnostic triad

o Secretory diarrheao High levels of circulating VIP > 150pg/mlo A pancreatic tumor

• Localizationo SRS - 91% of primary tumors and 75% of metastases.

Nikou GC, et al. Hepatogastroenterology  2005

• Management Correction of metabolic abnormalityOctreotide

Glucagonoma• Tumor of islet alpha cells• Mainly body and tail• 1% of all neuroendocrine tumors• Mean age of 55 years (19-84 years).• Nearly all are malignant • Migratory necrolytic erythema• 4D syndrome (dermatitis, diabetes, diarrhea, DVT)• Plasma glucagon >1000pg/ml: Diagnostic

Somatostatinoma• Rare• 70% to 90% of tumors – malignant• Location – usually head• Clinical findings – unpredictable

o Diarrhea o Gallstones – 59 %o Steatorrheao Mild diabetes – 75%

Pancreatic Endocrine Tumors in MEN 1• Pancreatic endocrine tumors -80% MEN 1 • Patients with MEN 1 -decreased life expectancy• Nonfunctioning pancreatic endocrine tumors –

most common 80-100% of cases• Gastrinomas -most common functional tumor-

60% of MEN 1

Surgical management • Surgical resection - the only curative treatment

for pancreatic neuroendocrine neoplasms • Management is similar for functional and non

functional tumors

Surgical management • Management of low risk disease - local

resection/enucleation preferred, observation is an option in benign NF - PNETS

• When the tumor is located further than 2-3 mm from the pancreatic duct, an enucleation preferred to pancreatic resection

• node metastases higher for tumors >15 mm, tumors in the head as compared to tumors in the body and the tail, tumors with higher proliferation rates(G3), and with lymph vessel invasion (L1)

Management of high risk/malignant disease• Extensive surgery is superior to conservative

therapies in extending patients’ survival and in controlling local and metastatic disease

• Survival advantage in all stages • reduce the risk for the development of

metachronous liver metastases• a margin-positive resection in locally advanced

PNETs seems to offer a similar overall survival compared to margin-negative resections(Pomianowska E, et al )in G1 and G2 tumors

Surgical Treatment of PNETs with resectable

synchronous liver metastases and no

extrahepatic metastases

The conditions that have to be assessed preoperatively• (1) the absence of extra-abdominal disease,• (2) the presence of low proliferative index (Ki67)

(G1 or G2), and • (3) the existence of somatostatin receptors in

order to deliver radiolabelled therapies as they resulted effective after cytoreductive surgery

Surgical Treatment of PNETs with resectable

synchronous liver metastases and no

extrahepatic metastases• a radical liver resection - possible only in 10% of the

patients• The 5-year survival of patients treated with hepatic

resection ranges from 47 to 76% and this compares well with the 30–40% 5-year survival in untreated patients

• rate of tumor recurrence is high, up to 76%• If staged procedures are required, liver resection should

be performed first, followed by pancreatic resection, due to the risk of seeding the biliary tract

Surgical Treatment of PNETs with

unresectable synchronous liver metastases

and no extrahepatic metastases

• Controversial •  surgical resection of at least 90% of all visible

tumor is possible in only 5% to 15% of patients with PNETs with hepatic metastases

• numerous uncontrolled studies provide evidence that surgical resection may improve symptom control and perhaps extend survival, neither result is proven at present (Falconi et al , Metz DC et al )

Primary tumour resection in metastatic nonfunctioning pancreatic endocrine carcinomas

• does not significantly improve survival. • Resection can be considered as symptomatic

palliative therapy in patients with well-differentiated endocrine carcinomas and a proliferative index lower than 10%

Liver transplantation The role of liver transplantation - experimental - overall 5-year survival - 45%, Le Treut YP et al

To optimize outcomes from liver transplantation include • age less than 50 years, • Ki-67 index of less than 2%, • tumors that stain for epithelial cadherin, and• lack of extra-hepatic metastasesA meta-analysis of 103 patients undergoing liver transplant for metastatic NETs reported an overall and disease free 5-year survival of 47% and 24% respectively (Lehnert T.et al )

Hepatic Artery Embolization/Chemoembolization

 a palliative option in patients with PNETs with hepatic metastases who are not candidates for surgical resection, have an otherwise preserved performance status, have disease primarily confined to the liver, and have a patent portal veinthe response rates  - 50%

RFA and Cryoablation•  either alone or in conjunction with cytoreductive surgery

Local ablation• Local ablative therapies include RFA, cryotherapy,

microwave coagulation, and ethanol injection• performed percutaneously or during surgery• complication rates of 5-15%, usually hematomas or

abscesses.• Successful local control of liver tumors occurs 85- 95%

of the time, symptom improvement from hormone excess occurs roughly 90% of the time

• 5-year survival of 48%

Management of pNET in MEN 1Surgical resection of small gastrinomas and non-functional pNETs in MEN1 is controversial.In favor of surgery • Up to 33% of patients with tumors <1 cm

already have metastatic disease and that early resection is the best chance to prevent development of metastases

• The most common operation is a distal pancreatectomy with enulceation of any tumors in the head of the pancreas

In favor of observation • Pancreatic resection has significant morbidity and mortality.• That given the underlying biology of the patient, resection

is rarely curative and most patients require re-operation.• Although metastatic pNETs are the leading cause of MEN1

related death, this accounts for only about 15% of mortality in MEN1 patients

• Even with metastatic disease, survival is generally excellent (roughly 50% 15-year survival rate for metastatic gastrinoma)

PNECs-high grade disease

• increased risk for recurrence and metastatic disease and survival is poor

• Resection only be attempted when an R0 resections seems possible

• no role for cytoreductive surgery• targeted therapies(e.g., VEGF and mTOR

inhibitors) are increasingly acknowledged to be superior to conventional chemotherapy

• Current - neoadjuvant chemo - reassess- surgery

Peptide receptor radiotherapy

• Coupling radioactive isotopes to SSAs, which enables selective delivery of radiotherapy to tumor cells

• Lu-177 labeled PRRT reported complete and partial tumor response in 2% and 28% of patients respectively with median overall survival 48 months

• PRRT is generally reserved for patients demonstrating progression of liver metastases

SOMATOSTATIN ANALOGS

• Used since 1980’s• Hormone blocking agents that are synthetic somatostatin

derivatives (ex: octreotide and lanreotide)• First line for neuroendocrine gastroenteropancreatic

tumors• 2nd -3rd line for insulinomas and gastrinomas• Side effects: development of gallstones secondary to

inhibition of cholecystokinin release, pain at site, hypo or hyperglycemia, rash, alopecia, fluid retention

Medical management Managing hormone excess – • Somatostatin analogs - octreotide (PROMID trial) 30 mg

intramuscular injection every 28 days or lantreotide (CLARINET trial)120 mg once in 28 days, targets somatostatin receptors that are overexpressed on most pNETs (except insulinomas)

• SSAs also seem to have cytostatic effects that can stabilize metastatic disease without tumor regression in most cases. 66.7% stable disease at 6 months compared to 37.2% for placebo

• The effect of these agents is most pronounced in tumors with a low proliferative index as they have a higher burden of somatostatin receptors

Targeted molecular therapy

Sunitinib and everolimus

Medical management

RADIANT - 3 TRIAL • a phase III prospective, double-blind, randomized, parallel-

group, placebo-controlled, multicenter study, involved 410 patients with advanced-, low-, or intermediate-grade pancreatic neuroendocrine tumors.

• receive either everolimus at 10 mg once daily or daily placebo,• median overall survival of 44 months vs  37.68 months • median progression-free survival vs placebo (11.0 vs 4.6

months)• stomatitis (46.7%), diarrhea (43.6%), and rash (40.0%).

Summary • Relatively rare tumors• The cornerstone of therapy for localized disease is surgical

resection• Cytoreductive surgery is generally indicated if greater than

90 percent of the tumor burden can be removed in G1 G2 tumors

• Most patients present with metastatic disease and will require a multidisciplinary therapeutic approach.

• Targeted molecular therapy - the new thing

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