FOCUS ON ENDOCRINE NEOPLASIA

Neuroendocrine Tumors

FAUSTO BOGAZZIUniversity of Pisa

Department of Endocrinology and Metabolic Disease Rome, 10 July 2010

Neuroendocrine TumorsThe origins

1897Identification of enterochromaffin cells Kulchitsky 1856-1925

1948 Isolation of serotonin (5-HT) Rapport M.

Foregut

Midgut

Hindgut

1953 Evidence of 5-HT in carcinoid tumors Lembeck F.

1963Introduction of carcinoid tumors embryologic classification (foregut, midgut o hindgut) Williams E.D. e Sandler M.

Siegfried Oberndorfer 1876-1944

1907 Introduction “karzinoide” concept (benign features)

1929 Identification of malignant and metastatizing neuroendocrine tumors

Neuroendocrine TumorsEpidemiology

Lung Appendix Stomach ColonSmall Bowel Recto Cieco Pancreas

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1 Oberg et al. ESMO Guidelines Working group. Ann Oncol 2009; S4: 150-1532 Newton JN et al. Br J Cancer 1994; 70: 939-42

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

Rare tumors: incidence 2.5-5/100,000/year in USA1

(largest group: small intestinal neuroendocrine tumors → 2.4/100000/y) 1

incidence 0.7/100000/year in Europe2

Higher incidence at autopsy: 8.4/100000/year1

Increasing incidence in the epidemiologic registry of USA3

100.000

Cases (

n)

0

1.000.000

Prevalence (database SEER)

1.200.000

NET Stomach Pancreas EsophagusColon - recto Liver

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

NET are the second most common tumors of gastrointestinal tract

Neuroendocrine TumorsEpidemiology

1.Oberg et al. ESMO Guidelines Working group. Ann Oncol 2009; S4: 150-153.2.Modified from Vierimaa et al. Eur J Endocrinol 2007; 157: 285-294

NET can appear at all age

Higher incidence from the fifth decade

Appendix carcinoid higher incidence at <30 years Patients with MEN1 or vHL: clinical onset 15 years earlier than sporadic forms

Neuroendocrine TumorsEpidemiology

Modlin IM et al. Lancet 2008.

Mortality

at the moment is nearly stable

Neuroendocrine TumorsEpidemiology

Hauso et al. Cancer 2008; 113: 2655-64Panzuto et al. Endocrine-Related Cancer

2005;12: 1083-92.

Mortality depends on:

Neuroendocrine TumorsEpidemiology

Site of NET Age at diagnosis Primary tumor dimension Tumor degree differentiation (ki67) Disease stage

Manifestation depends on:

Site of primary tumor

Functioning of the tumor

Non functioning NET: symptoms due to “mass effect” or distant metastases

Functioning NET

Paraneoplastic Syndrome: Cushing Syndrome, Acromegaly

Neuroendocrine TumorsClinical Manifestation

Tumor Syndrome Hormones Site

Carcinoid tumor Carcinoid Syndrome Serotonin, tachichinin, bradichinine, histamine Midgut Foregut

Insulinoma Hypoglycemia Insulin Pancreas

Glucagonoma Becker Syndrome (hyperglicemia, migrating necrolitic eritema) Glucagone Pancreas

Duodenum

Gastrinoma Zollinger-Ellison Syndrome Gastrin Pancreas Duodenum

VIPoma Diarrea ipokaliemia-achloridria VIP Pancreas

Lung

Neuroendocrine TumorsDiagnosis

1. Kloppel et al. ENETS Guidelines . Neuroendocrinology 2009: 90-162-169

Need of a documented hystopathological diagnosis

Biopsy

Resection Specimen

TNM classification

Oberg et al. ESMO Guidelines Working group. Ann Oncol 2009; S4: 150-153; Kloppel et al. ENETS Guidelines . Neuroendocrinology 2009: 90-162-169

.

Neuroendocrine TumorsDiagnosis

TNM classification

specific for different sites

Gastric Duodenum/ampulla/proximal jejunum

Pancreas Lower jejunum/ ileum

Grading Proposal for foregut (neuro)endocrine tumors

Grade Mitotic count (10HPF)a Ki-67 index (%)b

G1 <2 ≤ 2

G2 2-20 3-30

G3 >20 >20a 10 HPF: high power field= 2mm2, at least 40 fields (at 40x magnification) evaluated in areas of highest mitotic densityb MIBI antibody: % of 2.000 tumor cells in areas of highest nuclear labeling

11

Neuroendocrine TumorsPathology and Staging predicts Prognosis

12

Neuroendocrine TumorsGrading Predicts Prognosis

Clinical Syndrome Tumor Location Secretory Products Causing the Syndrome

Carcinoid SyndromeLung, Stomach and Pancreas (Foregut )Ileum and Jejunum(Midgut)

Serotonin, Histamine, Tachykinins, BradykininSerotonin, TachykininsBradykinin

Zollonger Ellison Syndrome Pancreas Duodenum Gastrin

Hypoglycemic (insulinoma) Pancreas (Sareomas) Insulin, proinsulin IGF-I/II, VIP, PHM

Verner-Morrison Syndrome Pancreas, Ganglioneuro-mas, Paraganglioma, Lung VIP, PHM

Glucagonoma Syndrome Pancreas Glucagon, (Glicentin)Somatostatinoma Syndrome Pancreas, Duodenum Somatostatin

“Non functioning” Tumours Pancreas, Colon CgA, HCG-α/β, PP, PYY (no endocrine related symptoms)

Neuroendocrine TumorsDiagnosis

Neuroendocrine TumorsCarcinoid Syndrome

Histopathology Argyrophil/argentaffin staining CgA, Serotonin

Tumour Markers CgA, u-5-HIAA, p-NPK, p-Subst-PP-ACTH, pCRF, PGHRH, s-calcito-nin, p-ADH, s-PP, s-HCGα/β, u-Histamine

Other Markers

Stimulatory Tests Flush provocation: Pentagastrin 0,6ug/kg bw i.v., measuring p-NKP every 5 min for 30 min

Radiology Octreoscan (111Ind-DTPA-octreotide)CT, US, MRI, (CT-angiography)

Other Investigations Endoscopy (endoscopic ultrasound)

Neuroendocrine TumorsCarcinoid Tumour Diagnosis

Tumour Location Pancreas 50-60%Duodenum 40-50%(sometimes both, MEN-I)20-25% Related to MEN-150-70% Malignant (lymphnode metastases)Gastrinoma Triangle 80%

Symptoms GastritisRecurrent ulcersDiarrhea (malabsorption)

Neuroendocrine TumorsZollinger Ellison Syndrome

Tumour Location Pancreas>90% malignant

Symptoms Necrolytic migratory erythema

Weight loss

Anemia

Trombosis

Impaired glucose tolerance

Diarrhoea

Neuroendocrine TumorsGlucagonoma Syndrome

Neuroendocrine TumorsGlucagonoma Syndrome

Tumour Location PancreasLungGanglioneuromas>80% Malignant(Pancreatic “nesidioblastosis”)

Symptoms Watery diarrhea (secretory) 3-20 litres/dayHypokalemia, Hypomagnesemia,HypercalcemiaAcidosisFlushingFlaccid distended gallbladderIleus/subileus

Neuroendocrine TumorsVerner-Morrison Syndrome (WDHA:s)

Tumour Location DuodenumPancreasColon/Rectum>80% mixed tumours

Symptoms GallstonesSteatorrheaImpaired glucose toleranceOften “non-functioning” tumours!

Neuroendocrine TumorsSomatostatinoma Syndrome

Neuroendocrine TumorsDiagnosis

O’Toole et al. ENETS Guidelines. Neuroendocrinology 2009; 90: 194-202

Biochemical Markers: Chromogranin A Recognized general serum marker →co-secreted in tumors with amines and

peptides present in neurosecretory granules Can be elevated in functional and non-functional NET More often high in midgut NET and non-functioning pancreatic NET Levels depending on: tumor cell type, differentiation, tumor volume

Neuroendocrine TumorsDiagnosis

O’Toole et al. ENETS Guidelines. Neuroendocrinology 2009; 90: 194-202

Biochemical Markers: Urinary 5-HIAA In carcinoid syndrome sensitivity 70%, specificity 90% Most frequently high in midguts carcinoid than fore- and hindgut tumors Depends on tumor volume, often normal in non metstatic carcinoids At the moment can’t be considered a reliable prognositc factor Use of HPLC has to be preferred

Falsely low: Renal impairment

Falsely high:Malabsorption (coelic disease,

intetsinal stasis, cystic fibrosis); DRUGS (FANS); FOOD (TRIPTOFAN-RICH)

Neuroendocrine TumorsDiagnosis

O’Toole et al. ENETS Guidelines. Neuroendocrinology 2009; 90: 194-202

Biochemical Markers: Gastrin Useful to diagnose Zollinger-Ellison Syndrome Elevated fasting serum gastrin Low gastric pH Secretin test: ∆ gastrin increase ≥110 pg/ml (sensitivity 93%)

∆ gastrin increase ≥200 pg/ml (sensitivity 85%) ∆ gastrin increase ≥ 120 pg/ml (sensitivity 94%;specificity 100%)

Neuroendocrine TumorsDiagnosis

O’Toole et al. ENETS Guidelines. Neuroendocrinology 2009; 90: 194-202

Biochemical Markers: Insulin Useful to diagnose Insulinomas

I. Symptoms of hypoglicemiaII. Glucose < 40-50 mg/dlIII. Relief of sympoms with glucose administration

Whipple’s Triad

72h fast→ gold standard for diagnosing insulinoma To attest: Failure of appropriate

insulin suppression Autonomus insulin secretion

Test endpoint: document hypoglycaemia blood glucose ≤ 2.2 mmol/L (≤ 40 mg/dL) [or <3 nmol/L, 50 mg/dL] concomitant insulin levels > 6 μU/L (≥ 36 pmol/L) A β-hydroxybutyrate level ≤ 2.7 mmol/L ( confirm test validity and inappropriate insulin suppression)

A glucagon test immediately after 72-hour fasting in patients without definitive results recommended

Use of a ratio insulin to glucose is not recommended to aid diagnosis Exercise test immediately after 72 hours fasting in patients without definitive results only in

supervised setting

Total BodyScreening and Staging

Octreoscan (111Ind-DTPA-octreotide) (SRI)Sensitivity <10 mm 40% >10 mm 90%Liver metastases = 90%

Disclosure of Endocrine Pancreatic Tumours

Endoscopic ultrasonography(EUS); sensitivity <10 mm ≈ 50%SRI + EUS sensitivity <10 mm ≈ 90%

Newer Techniques Positron emission tomography with

C11-5 HTP or C11-L-dopa (PET)Traditional Techniques (always a complement)

CT (+ angiography), MRIUS; sensitivity small tumours 10-30%Liver metastases 90%

Neuroendocrine TumorsRadiology of Neuroendocrine Tumours

Neuroendocrine TumorsDiagnosis - Imaging

Table 5: Ramage JK, et al. Gut 2005; 54: 1-16.

Imaging

Scan speed

multidector TC Contrastographic study with acquisition in different phases

Precocious

Arterial (20’’)

Pancreatic (35’’)

Venous (70’’)

Fenchel S et al Eur J Radiol 2003 Horton, Radiographics 2006 Rha, Eur J Radiol 2007

Neuroendocrine TumorsDiagnosis - Imaging

Multidetector TC : gastrointestinal lesions

Neuroendocrine TumorsDiagnosis -Imaging

Octreoscan

Neuroendocrine TumorsDiagnosis -Imaging

Ecography

Neuroendocrine TumorsDiagnosis -Imaging

Neuroendocrine TumorsThe Ultimate Goals for the Treatment of Neuorendocrine Tumours

•Total eradication by surgery (not possible in most cases)

•Abrogation of tumor growth and/or amelioration of clinical symptoms

•Improving and maintaining a good quality of life

Neuroendocrine TumorsTherapy of Neuroendocrine Gut and Pancreatic Tumours

Surgery

Embolisation ± Chemotherapy

Irradiation

Medical Treatment

conventional for bone metastases

experimental (local)

Somatostatin Analogues

α-Interferon

Chemotherapy

even palliative and tumors reduction

111Ind-DTPA-octreotide 45-60 Gy90 Y-DOTA-octreotide

Kaltsas et al. Endocrine Reviews 2004, 25(3): 458-511

first line therapy in localized NET

Neuroendocrine TumorsSurgical Therapy

Important role in hepatic metastatic disease

Neuroendocrine TumorsSurgical Therapy

Neuroendocrine TumorsEmbolisation of Liver Metastases

Biochemical Response Tumour Response

Embolisation(Spongostan®, Gel-Foam) 30-50%

Median duration20-30%

7-10 months

Chemoembolisation(Doxorubicin) 50-80%

Median duration40-50%

10-20 months

PROLIFERATION

DIFFERENTIATION

Biotherapy SSA IFN-α

Chemotherapy

Neuroendocrine TumorsProposed TNM classification and NET therapy

Grading Proposal for foregut (neuro)endocrine tumors

Grade Mitotic count (10HPF)a Ki-67 index (%)b

G1 <2 ≤ 2

G2 2-20 3-30

G3 >20 >20a 10 HPF: high power field= 2mm2, at least 40 fields (at 40x magnification) evaluated in areas of highest mitotic densityb MIBI antibody: % of 2.000 tumor cells in areas of highest nuclear labeling

Neuroendocrine TumorsINF-α Treatment

Subjective Response 50-70%

Biochemical Response 30-70%

Tumor Response 10-15%

Neuroendocrine TumorsSomatostatine Receptors

• Five subtypes cloned: SSTR 1-5

• SOM.14 and 28 bind to all receptor subtypes

• All receptor subtypes are 7 TM receptors and G-Protein coupled

• Effector mediators are C-AMP, CA2+ /K+ FLUX, TYROSINPHOSPHATASES

• Octreotide binds to SSTR2 and SSTR5

• SSTR2 mediates biochemical and tumour responses

• SSTR3 mediates apoptosis

• SSTR5 mediates anti-tumour response different from SSTR2 (NOT VIA PTPI-C BUT CA 2+ /K +FLUX?)

Neuroendocrine TumorsOctreotide Treatment

Subjective Response 30-75% (dose dependent)

Biochemical Response 30-60% (dose dependent)

Tumor Response 0-15% (not dose dependent)

Time (months)

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Tachifilaxis: Hormone secretion

Hofland, Endocrine Review 2003

Somatostatine Analogs

Neuroendocrine TumorsMedical Therapy

Tachifilaxis: antiproliferative effectWynick D, Clin Endocrinol (Oxf). 1989 Resistance of metastatic pancreatic endocrine tumours after long-term treatment with the somatostatin analogue octreotide.

Lamberts SW, Acta Endocrinol (Copenh).,1988Development of resistance to a long-acting somatostatin analogue during treatment of two patients with metastatic endocrine pancreatic tumours.

Koelz A Gastroenterology. 1987Escape of the response to a long-acting somatostatin analogue (SMS 201-995) in patients with VIPoma.

Neuroendocrine TumorsChemotherapy of Neuro-Endocrine Gut and Pancreatic Tumours

ResponseRate

Endocrine pancreatic Tumor Streptozocin + 5 FU 40-60%

Streptozocin + doxorubicin ≈ 60%

Cisplatinum + Etoposide(low differentiated tumors)

≈ 50%

Taxol + doxorubicin ≈ 40-50%

Midgut Carcinoid Tumours Streptozocin + 5 FU 10-30%

Cisplatinum + Etoposide 10-15%

Neuroendocrine Tumors PRRT:

Effects depending on: Radiosensibility:

Growth pattern of the tumor DNA repair

Concentration of radioactivity on the tumor (adsorbed dose)

Reubi JC et al. Eur J Nucl Med 2000

Receptorial affinity of radiopeptides

Receptorial density on the tumors and other organs

Mts linfonodali node mets

from paraganglioma

< liver

Mts linfonodali

da NET GHRH-sec.

> liver» kidney& spleen

VIP-secr.pancreatic NET

Pharmacokinetic: fast plasmatic clearance and renal excretion

Neuroendocrine Tumors PRRT:

Response: predictive factors

Elevated uptake Presence of liver metastasis

Progression: predictive factors

Elevated Ki-67 Higher tumor mass

New prospective will be available..

New Therapies

Neuroendocrine TumorsMedical Therapy:

At the moment drugs used only in clinical trialsModlin et al. Lancet Oncology 2008; 9: 61-72

Neuroendocrine TumorsConclusions

NET are rare neoplasms and they still remain orphan tumors with a survival that is

stable over the past three decades

Many physicians are involved in the management of NET having to cooperate daily

Therapeutic strategies must be individualized depending on tumor type, site, spread,

symptoms and general condition of the patient

We still need..• More reliable markers• Better tumor localization• Cell lines and models to define biology, behavior and genetics• More numerous and randomized trials• To develop molecularly targeted therapies• Centres of excellence and NET clinical teams to coordinate multicentre

studies, extend clinical and tissue databases

Vasily Kandinsky Several Circles 1926 oil on canvas; Solomon R. Guggenheim Museum, New York

Thanks for your attention

Acknowledgments

Enio Martino Luca Manetti Sandra Brogioni Chiara Sardella Isabella Lupi Chiara Cosci Luca Tomisti Enrica Dell’Unto Martina Lombardi Claudio Urbani Ilaria Scattina Valentina Raffaelli Francesco Raggi Dania Russo