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Prof. Wouter W. de HerderAfdeling Inwendige Geneeskunde

Sector EndocrinologieErasmus MCRotterdam

Prof. Wouter W. de HerderAfdeling Inwendige Geneeskunde

Sector EndocrinologieErasmus MCRotterdam

GEP - NETGEP - NET

• Wat is een GEP-NET?

• Voorkomen GEP-NET.

• Indeling GEP-NET.

• Therapie GEP-NET.

• Carcinoïd.

• Steve Jobs.

• Insulinoom.

Programma

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Bloedbaan

ENDOCRIEN

NEUROENDOCRIEN /NEUROTRANSMITTER

Neuroendocrien Systeem

• Hypofyse

• Parafolliculaire cellen van de schildklier

• Bijniermerg

• Endocriene pancreas(alvleesklier)

• Diffuus neuro-endocrien systeem

(maag-darm, long, huid………)

Hypofyse

Bijniermerg

SchildklierC-cellen

Pancreas

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Endocriene Cellen in het (Neuro)endocriene System v an de Maag-Darm Tractus en Alvleesklier (Pancreas)

Cel

P/D1ECDLAPPBXECLGCCKSGIPMN

Product

GhrelineSerotonine

SomatostatineGLI/PYY

GlucagonPP

Insuline?

HistamineGastrine

CCKSecretine

GIPMotiline

Neurotensine

foetusenige

+

+++

+++

foetus

enige+

+++

+

enige++

enige

foetus

+++++

enige

+enige

+

+++++

+enige

+

+++

enige

enigeenige

+

+enige

+

+++

GEP Systeem= Gastro Entero Pancreatische Systeem

NET= NeuroEndocriene Tumor

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Gastroenteropancreatische (Neuro)endocriene Tumoren (GEP-NET)

Tumor

Gastrinoom

Insulinoom

VIPoom

Glucagonoom

Somatostatin-oom

Carcinoïd

Hormoon

Gastrine

Insuline

VIP

Glucagon

Somatostatine

SerotonineTachy-en

bradykinines

Aantal permiljoen

personen / jr.

0.5-1.5

1-2

0.05-0.2

0.01-0.1

20-50

Symptomen (Klachten)

Maagulcera, >>diarree

Hypoglykemieën

>>>>Diarree, opvliegers

Diabetes, huiduitslag, extreme vermagering

Galstenen, vettigeontlasting, diabetes

>>Diarree, opvliegers, hartklepziekten,

darm verstopping

Toename Incidentie van GEP/Long NET

2

0

1

3

4

5

6

0

100

200

300

400

500

600

5.25

Jaar74 76 78 80 82 84 86 88 90 92 94 96 98 00 02 04

Incidentie van alle maligniteiten

Incidence van neuroendocriene tumoren

Inci

dent

ie v

an N

ET

per

100

,000

Inci

dent

ie v

an a

lle m

alig

ne n

eopl

asm

ata

per

100,

000

De incidentie en prevalentie van NET is ongeveer 50 0% toegenomen over de afgelopen 30 jaar!!

Yao JC, et al. J Clin Oncol. 2008;26:3063-72.

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NET

Functioneel Niet-functioneel

Morbiditeit en mortaliteit gerelateerd aan:•Hormonale or hormoon-gerelateerde symptomen/syndromen•Tumor expansie

Functioneel versus Niet-functioneel NET

Morbiditeit and mortaliteitgerelateerd aan:•Tumor expansie

Modlin IM, Öberg K. A century of advances in neuroe ndocrine tumor biology and treatment. 1st edition. Hannover: Felse nstein CCCP; 2007.

Proliferatie MarkersKi-67

Laag Hoog

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Pancreas

Hyperplastic and preneoplastic lesions

Neuroendocrine tumor, NET G1(Well-differentiated)

Neuroendocrine tumor, NET G2(low-grade malignant)

GI tract

Hyperplastic and preneoplastic lesions

Neuroendocrine tumor, NET G1(“carcinoid”)

(Well-differentiated)

Three-tier System for GEP NET

Bosman FT, Carneiro F, Hruban RH, Theise ND WHO Cla ssification of Tumours of the Digestive System, 2010

Neuroendocrine carcinoma, NEC (small or large cell type)Mixed adeno-neuroendocrine carcinoma, MANEC

(high-grade malignant)

Improvement of NET Grading System using Mitoses and Ki-67

Grading proposal for foregut NET

GradeMitotic count (10

HPF)Ki-67 index

(%)

G1 < 2 ≤ 2

G2 2–20 3–20

G3 > 20 > 20

Rindi G, et al. Virchows Arch. 2006;449:395-401. Pap e UF, et al. Cancer. 2008;113:256-65.

Cum

ulat

ive

surv

ival

0 50 100 150 200 250 300

Survival time (Months)

0

0.2

0.4

0.6

0.8

1.0

Grading using Ki67

G1G2

G3Univariate analysis:

G1 vs. G2: p = 0.040

G1 vs. G3: p < 0.0001

G2 vs. G3: p < 0.0001

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• Lokaal:

• buikklachten• buikpijn• darm verstopping

• Systemisch:

• Afgifte van mediatoren • in aanwezigheid van lever metastasen bij patiënten met dunne darm carcinoïden of long carcinoïden

carcinoïd syndroom

CarcinoïdenSymptomatologie

Carcinoïd SyndroomSymptomatologie

• Flushing, teleangiectasieën en pellagra dermatitis

• Diarree en buikkrampen

• Fibrose van het endocardium van het rechter hart, m et o.a. als gevolg tricuspidalis en pulmonalis klep stenose en insufficiëntie

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CT Scan Abdomen (Buik) (transversale coupes) en Pathologie

Binding van Somatostatine en de Analogen Octreotide, Lanreotide en Pasireotide

aan de Somatostatine Receptor Subtypen

SomatostatineOctreotideLanreotide PasireotidePasireotide

sst 1 sst 2 sst 3 sst 4 sst 5

TUMOR

Somatostatine Receptor Subtypen (sst)

op het tumor oppervlak

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Moertel J. J Clin Oncol. 1987;5:1502-22.

Verbetering bij patiënten (%)

Flushing(n=53)

Diarree(n=48)

5–HIAA(n=57)

> 50% verbetering

Complete verbetering

0 25 50 75 1000 25 50 75 100

Somatostatine Analoog Behandeling van het Carcinoïd Syndroom

111In-pentetreotide Scintigrafie

Gem

etas

tase

erd

Rec

tum

Car

cino

ïd

Gem

etas

tase

erd

Thy

mus

Car

cino

ïd

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Targeted Somatostatine Analogen?

Radioactief gelabelde somatostatine

analogen?

Cytotoxische somatostatine

analogen?

TUMORcell

I [111In-DTPA0,DPhe1]octreotide

II [90Y-DOTA0,DPhe1,Tyr3]octreotide

III [177Lu-DOTA 0,DPhe1,Tyr3]octreotaat

10 µm (+ gamma) “ ≤ 1 cel”

“150 cellen”

“20 cellen” (+ gamma)

Weefsel-Penetratie

Somatostatine Analogen voor sst 2 Moleculaire Radiotherapie in het Erasmus MC

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90Y/177Lu

90Y/177Lu

Auger electronen en alfa emitters: korte doordringb aarheid ( 111In) ββββ emitters: langere doordringbaarheid ( 177Lu (1-2 mm), 90Y (12 mm))

111In

Radionuclieden

111In

111In

12

?

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Clinical Case: Case History and Lab.

A 50-year-old male presented with hypoglycemic coma after a shortperiod of fasting prior to a planned gastroduodenoscopy for upper GIbleeding.At upper GI endoscopy, gastritis and duodenitis were diagno sed,which were probably caused by the use of carbasalate calcium .He had started using this therapy after a transient ischemic attack,which was diagnosed the previous year.

Already at the time of the transient ischemic attack, a rando m fastingplasma glucose level of 48.6 mg/dL (2.7 mmol/L) was measured , butno action was undertaken.

The fasting laboratory tests were: • Plasma glucose: 18 mg/dL (1.0 mmol/L).• Insulin: 173 pmol/L. • C-peptide: 4.65 ng/mL (1.55 nmol/L).

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Biochemical Diagnosis of Organic Hyperinsulinism

• Blood glucose level less than 2.2 mmol/L (less than 40 mg/dL)during symptoms.

• Concomitant insulin levels ≥≥≥≥6 IU/mL ( ≥≥≥≥43 pmol/L).[>3 IU/mL / >18 pmol/L (ICMA)].

• Concomitant C-peptide levels ≥≥≥≥0.2 nmol/L.

• Concomitant pro-insulin levels ≥≥≥≥5 pmol/L.

• Absence of sulphonylurea, thiazolidinedione (metabolite s) in theplasma or urine

• ß-hydroxy-butyrate <2.7 mmol/L at end of fast

• glucose response to 1 mg. glucagon >1.4 mmol/L at end of fast

Service FJ, N Engl J Med 1995: 332, 1144-52.

• C-peptide: 4.65 ng/mL (1.55 nmol/L).

• Insulin: 173 pmol/L

• Plasma glucose: 18 mg/dL (1.0 mmol/L)

Differential Diagnosis of Hypoglycemia (1/2)

• Endogenous hyperinsulinism:• Insulinoma

• Nesidioblastosis

• Auto-antibodies

• Abuse of sulfonylurea derivatives

• Exogenous hyperinsulinism

• Deficiency of counter-regulatory hormones• Addison's disease• Hypopituitarism (children)

• Liver failure

• Bilroth II stomach operation (dumping) – Gastric byp ass/banding

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Differential Diagnosis of Hypoglycemia (2/2)

• Renal failure

• Ethanol intoxication

• Medication• Salicylates

• Quinine

• (Big) IGF-II-producing (mesenchymal) tumors

• Inborn errors of metabolism• Glycogen storage disease• Hyperinsulinism/hyperammonemia syndrome

Clinical Case: CT

Hypervascular, partially necrotic pancreatic mass w ith thrombosis of the splenic vein and multiple liver metastases

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Increaseduptake in the

pancreatic lesion as well as in the liver metastases

Clinical Case: OctreoScan

Well-differentiated, WHO2010 grade 1, neuroendocri ne tumor with a Ki-67 index of <2% and

positive immunohistochemistry for insulin.

Clinical Case: Pathology Pancreatic Mass

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Treatment Interventions in Malignant Insulinoma (1/2)

Control of hypoglycemias;

• Frequent meals.• Nocturnal feeding via nasogastric tube.• iv Glucose.

• Diazoxide.

• Diphenylhydantoin.

• Somatostatin analogs.

Treatment Interventions in Malignant Insulinoma (2/2)

• Anti-tumor therapies:• Cytoreductive surgery (debulking).

• Liver directed therapies:• Embolization/Chemo-embolization.• Radiofrequency ablation (RFA).• Laser-induced thermotherapy (LITT).• Selective internal radiotherapy (SIRT) using 90Yt

microspheres.

• Cytotoxic chemotherapy / targeted therapy (Everolim us, Sunitinib).

• Peptide receptor radiotherapy (PRRT).

• Somatostatin analogs? / Alpha interferon's.

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Clinical Case: Treatment Interventions

van Schaik, et al . J Clin Endocrinol. Metab, 2011;96:3381-3389.

Clinical Case: Treatment Interventions PRRT

van Schaik, et al . J Clin Endocrinol. Metab, 2011;96:3381-3389.

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• Wat is een GEP-NET?

• Voorkomen GEP-NET.

• Indeling GEP-NET.

• Therapie GEP-NET.

• Carcinoïd.

• Steve Jobs.

• Insulinoom.

Summing-up