NEUROENDOKRIN

TUMOR
Origin:

Neuropeptides

Catecholamines

Hormonal
Syndromes

Lawrence B, Gustafsson BI, Chan A, et al. The epidemiology of gastroenteropancreatic neuroendocrine

tumors. Endocrinol Metab Clin North Am 2011; 40:1.
 Incidence of NETs Is Increasing*
1.40 NET Site
Incidence Per 100,000

1.20 Lung
Colon
1.00 Small intestine
Rectum
Pancreas
0.80

0.60

0.40

0.20

Year
*Approximate 5-fold increase between 1975 and 2004
Approximate 7-fold increase also evident in Norwegian registry
SEER = Surveillance, Epidemiology, and End Results (for malignant NETs)
Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:3063-3072.
3 3
NETs Are the 2nd-Most Prevalent
Gastrointestinal Tumor:
NET Prevalence in the US, 2004
1,200

Median survival (1988

103,312 Localized
2004) 203 months
1,100 cases Regional 114 months
(35/100,000) Distant 39 months
No. of cases
(thousands)

100

Colon Neuroendocrine Stomach Pancreas Esophagus Hepatobiliary

29-year limited duration prevalence analyses based on SEER

Adapted from: Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072.

NET: Demographics:

Lepage C, et al. Gut. 2004;53(4):549-553.

Primary Tumor Localizations
thymus (1%)
est. % of all NEN
bronchus (-15%)
thymus <1
bronchus 15
esophagus <1 esophagus (<1%)

stomach 15
duodenum 4
pancreas 15 pancreas (-15%) stomach (-15%)

jejunum/ileum 15
duodenum (-4%)

cecum 2
appendix 15 ascending
colon (-
1%)
jejunum (-5%)

colon 1
rectum 10 ileum (-10%)

cecum (-2%)

appendix (-15%)
descendin
rectum (-10%) g colon
(<1%)
sigmoid
colon (-
12%)
Pape UF, et al. Gastroenterol up2date. 2011;7:313-
339.
Hormone Hypersecretion Syndromes
(= Functioning NET)
Functioning: 39.5% (553)
Non-functioning: 60.0% (836)
Unclear: 0.5% (11)

Calcitonin 1

Somatostatinoma 2

Cushing syndrome 6

Atypical carcinoid syndrome 5

Verner Morrison syndrome (VIPom) 8

Glucagonoma 16

Gastrinoma 76

Insulinoma 158

Carcinoid syndrome 244

0 20 40 60 80 100 120 140 160 180 200 220 240

Begum N, et al. Zentralbl Chir. 2014;139(3):276-283.

 Pathogenesis of Carcinoid:

Enterocyte
Enterocyte

Enterocyte
Enterocyte

NE-cell

Rindi G, Wiedenmann
B. Nat Rev Endocrinol.
2011;8(1):54-64
Pathogenesis of Carcinoid:
TRYPTOPHAN METABOLISM

NORMAL NET

1% 70%

SEROTONIN SEROTONIN

FOREGUT MIDGUT HINDGUT

Pathogenesis of Carcinoid:

Marc Dez, Alexandre Teul, Ramon Salazar. Ann Gastroenterol 2013; 26 (1): 29-36
NET: Not all the same:

Biologicalbehavior
Malignant
Uncertain
Benign

Niederle MD, et al. Endocr Relat Cancer. 2010;17(4):909-918.

Key Issues in The Management:
1. How do we define the disease?
Nomenclature, Classification & Pathology.
2. Who needs treatment and when?
Patient Selection.
3. Which treatment and in what sequence?
Treatments.
4. What is the role of combined biologics,
somatostatin analogues, cytotoxics and
biomarkers?
Unanswered Questions.
 Evolution of Terminology & Classification:
Historic Evolution:
1907 1963 1970 1980 1995

Williams & Soga & WHO Capella

Sandler Tazawa

Histologic Granular Size &

Stain Invasion
Carcinoid Techniques

Benign.
Benign or Low
Grade Malignant.
Low Grade
Malignant.
No Prognostic or Predictive
High Grade
Validation
Malignant.
Neuroendocrine Neoplasms

H.E. synaptophysin

MIB-1/Ki67 CgA
Evolution of Terminology & Classification:
Histopathologic Differentiation:
Differentiated
Well
Differentiated
Poorly
Evolution of Terminology & Classification:
AJCC Criteria of Grading:

Grade Mitotic Ki 67
Count (per Index (%)
10 HPF)
G1 <2 <2
G2 2 20 3 20
G3 > 20 > 20

AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer New York, Inc.
Prognostic Influence of Ki67-Labelling
< 2% 15% 75%

Pape UF, et al. Endocr Relat

Cancer. 2008;15(4):1083-1097.

Ekeblad S, et al. Clin Cancer Res. 2008;14(23):7798-

7803. Vilar E, et al. Endocr Relat Cancer. 2007;14(2):221-
232.
Scarpa A, et al. Mod Pathol. 2010;23(6):824-
833.
 Evolution of Terminology & Classification:
Correlation of TNM Staging With Survival:
Patients With Well-Differentiated Pancreatic NET
1.00
Stage I

0.75
Proportion Alive

Stage II

0.50

Stage III
I (n = 44)
0.25 II (n = 44)
III (n = 34)
IV (n = 33)
P<0.001
0.00 Stage IV
0 48 96 144 192 240
Time (mo)
La Rosa S, Klersy C, Uccella S, et al. Hum Pathol.
2009;40:30-40. 18 18
Evolution of Terminology & Classification:
NETs Are Often Diagnosed Late:
Estimated time to diagnosis: 5 to 7 yr
Death

Diarrhea *
Vague abdominal symptoms
Flushing *
Metastases

Primary tumour growth

1 2 3 4 5 6 7 8 9
Time (yr)

*Symptoms of carcinoid syndrome

Vinik AI, Silva MP, Woltering EA, et al. Pancreas. 2009;38:876-889.
Evolution of Terminology & Classification:
Metastatic Disease Is Common at Presentation:

27% Distant metastases

50%

23% Regional spread

Localized Metastatic
*These data are of the cases in which stage was reported.
20% of cases did not provide disease stage information

Data from an analysis of 28,515 cases of NET identified in the SEER registries
Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:3063-3072.
Immunohistochemical NE markers:

Pan-neuroendocrine markers

Cytosolic NSE, PGP 9.5

Related to secretory
Chromogranin
granules
Related to synaptic vesicles Synaptophysin, VMAT

Intermediate filaments NF, CK HMW

Adhesion molecules N-CAM

Circulating Tumor Markers:
Chromogranin A*
(in 70%-90% increased in metast. NET)

Pancreatic Polypeptide, PP
(in 40%-55 % elevated);

a-HCG, -HCG
(in ~ 30% elevated)

Neuron specific enolase (NSE)

(in ~33% elevated)

*The height of Chromogranin A level correlates with tumor load,

an increase over time indicates tumor progression
Diagnosis: Imaging Primary Tumor/Tumor
Spread:
Whole body Screening Octreoscan (111Indium-DTPA-
& Staging Octreotide)/ SPECT: 1. choice

Endocrine Pancreatic tumor Endoscopic ultrasonography

< 1cm

Routine imaging ultrasonography of the liver

CT (+ angiography), MRI

Primary tumour Screening Positron emission tomography (PET)

& Staging (optional) with 11C-5 HTP,11C-L-dopa or 18F-FDG
SMS-R-PET: 68Gallium-DOTATOC-
PET
PET/CT
ENETS-Guidelines 2011
3. Therapy for Advanced Disease
Symptom Control
& Cytotoxic Therapy
 Therapy of NETs
Three principles

Surgical Symptomatic Antiproliferative

therapy therapy therapy

Cure
Debulking Control of hormonal Control of tumor
Treatment / symptoms growth
Prevention of Improvement of
complications survival?
 Therapy of GEP-NETs: Shifting From
Symptom Management to Targeting Tumors

Somatostatin
analogues

Symptomatic therapy Control of

(carcinoid syndrome) tumor growth
Possible Mechanisms for Antiproliferative
Activities of SSAs
Antiproliferative effect of SSA

Binding to the somatostatin

Systemic effect
receptor on tumor cells

Direct antiproliferative effect Indirect antiproliferative effect

Inhibition Inhibition of
Inhibition Pro- Inhibition Immune
of growth angiogenesis
of cell apoptotic of growth system
factor modulation
cycle effect factor and
effects
trophic
hormones

Susini C, et al. Ann Oncol. 2006;17(12):1733-1742.

Somatostatin Receptors (SSTR) Are
Expressed by the Majority of NETs
Prevalence on NET type: SSTR1 SSTR SSTR3 SSTR4 SSTR5
2
Pancreas 68% 95% 46% 93% 57%
Midgut 80% 86% 65% 35% 75%
Inhibitory effect:
Hormone secretion + + +
Proliferation + + + +
Induction of apoptosis + +
SSTR2 is most prevalent in GEP-NETs and induces
inhibitory effects on hormone secretion and proliferation
in NETs
Somatostatin is effective in controlling NET-related
hormonal symptoms
Clinical use of somatostatin is limited by its short half life
Basu B, et al. Endocr Relat Cancer. 2010;17(1):R75-R90. Modlin IM, et al. Aliment Pharmacol Ther.
2010;31(2):169-188. Hofland LJ. J Endocrinol Invest. 2003;26(8 Suppl):8-13. Ferrante E, et al. Endocr Relat
Cancer. 2006;13(3):955-962.
NET Treatment Algorithm:
TAKE HOME MESSAGE:
NENs are heterogeneous, and we need to
deal with hormone release, tumor growth
rate and related symptoms
A different staging classification to other solid
tumors is used for NENs, joining TNM and grading
systems
SSAs are the cornerstone of therapy for
hormone- related symptoms and recently
showed their antiproliferative effect in G1/Low G2
enteropancreatic NETs
Better knowledge of molecular biology has
prompted the development of targeted therapies for
NETs, that should be integrated with SSAs,
chemotherapy, PRRT and loco- regional therapies