DIFFUSE HORMONAL SYSTEMS AND ENDOCRINE TUMOR SYNDROMES

Hasan AYDIN, MD; Yeditepe University Medical Faculty; Department of Endocrinology and Metabolism

THE ORIGIN OF NEUROENDOCRINE TUMORS

• NET originates from APUD (Amine Precursor Uptake and Decarboxylation) cells.

• APUD cells constitute the diffuse endocrine system of the body.

• Gastrointestinal tractus• Pancreas• Lung• Central nervous system• Skin• Adrenal medulla• Thyroid

Neuroendocrine Tumors Frequency

• Incidence: 1-2/100.000

• Autopsy series 8/100.000

• Carcinoid tumors are the most frequent type.(40% of all NETs)

CLASSIFICATION OF NET

• Well differentiated neuroendocrine tumor

• Well differentiated neuroendocrine carcinoma

• Poorly differentiated neuroendocrine (small cell) carcinoma

• Mixed endocrine tumors

WHO International Histological Classification of Tumours, Springer Verlag 2000

Classification of NETs of GEP system

• Carcinoid tumors– Foregut

• Bronchial carcinoid tumors

• Gastric carcinoid tumors

– Midgut• Small intestinal

carcinoid tumors• Apendix carcinoid

tumors– Hindgut

• Rectal carcinoid

• Pancreatic endocrine tumors

– Insulinoma– Gastrinoma– Glucagonoma– VIPoma– Somatostatinoma– PPoma

Carcinoid Tumors

• Analyses of 13,715 cases of carcinoid between 1950-1999 in USA:

75% located in gastrointestinal system

25% located in bronchopulmonary system.

Carcinoid Syndrome• Carcinoid syndrome:

– Vasomotor symptoms

• Flushing

• Tachycardia

• Hypotension

• Sweating

– Gastrointestinal hypermotility (diarrhea)

– Bronchospasm (wheezing, dispne)

• Carcinoid syndrome is seen in 10% of all gastrointestinal

carcinoid tumors.

Gastric Carcinoid Tumors• Constitute 4.1% of all carcinoid tumors and less than 1% of all

gastric neoplasms.

• Most frequently seen between age 50-60.

• There are 3 distinct types:

– Type 1: Associated with Type A chronic atrophic gastritis

– Type 2: Associated with Zollinger-Ellison syndrome

– Type 3: Sporadic gastric carcinoid tumors

Pancreatic Endocrine Tumors

• Estimated incidence 1-4 / 1.000.000.

• Can be a part of MEN-1 syndrome.

• Clinical presentation varies according to the hormone(s) secreted.

Insulinoma• Mostly seen in the 5-6 decades.

• Symptoms of hypoglycemia • Palpitation, sweating, nervousness, conscious disorders, coma etc

• The tumor size usually <1.5 cm.

• Usually cannot be detected with CT, MRI and angiography.

• EUS is the best method for pre-op localization of the tumor.

• Per-operative palpation and IOUS are the best methods to identify the tumor.

Gastrinoma• Usually presents with abdominal pain due to peptic ulcer

and diarrhea due to hypersecretion.

• Ulcers are seen in stamach, duodenum, esophagus and

intestines.

• Gastrinomas are associated with MEN-1in 25% of the

cases.

• Fasting gastrin level >100 pg/ml.

• Basal acid secretion is >15 mEq/hour.

• PPI are effective in supression of acid secretion

Frequency ( % )

Pancreatic (n=27) Intestinal (n=21)Sign/Symptom

Diabetes Mellitus 95 21

Gallbladder disease 94 43

Diarrhea 92 38

Steatore 83 12

Hypochlorhydria 86 17

Weight loss 90 69

Somatostatinoma

Diagnosis of Neuroendocrine Tumors

• Depends on each cellular type

• For correct diagnosis:

– Clinical symptoms

– Humoral biochemical tumor markers

– Stimulant (Provacative) tests

– Imaging techniques

– Histopathology (CgA, sinaptofizin, NSE)

Biochemical Tumor Markers

• Biochemical markers for NET:

– Nonspecific marker:

Plazma Chromogranin A (CgA)

– Specific marker(for carcinoid):

24-hour urine 5-HIAA

Provocation Tests for GEP/NET

Tumor Provacation tests

Carcinoid Pentagastrin test

Gastrinoma Secretin test

Insulinoma Extended fasting glucose test

VIPoma None

Glucagonoma None Somatostatinoma None

Octreotide Scintigraphy• Advantages

– High sensitivity.– Whole body imaging.– Predicts response to

octreotide therapy.

• Disadvantages

– Cannot detect tumors not expressing somatostatin receptors

-Somatostatin receptors including subtype 2 (sst-2) are present in

88-100% of carcinoid tumors.

-Lower tumor size limit 0.5 cm.

-Sensivity is around 90%.

Imaging of Neuroendocrine Tumours

• Ultrasound: low sensitivity for primary ~30%; metastases ~70%

• Spiral CT vs MRI: primary up to 70%; metastases 90%

• Octreotide scan: primary up to 80%; 95% metastases

• Endoscopic Ultrasound: ~95% pancreatic primary tumourgastric carcinoid; rectal

carcinoid

Symptom Control– General Measures• Insulinoma

– Potassium replacement

– IV dextrose administration

– Diazoxide

• Gastrinoma

– Correction of performance status

– Control of bleeding

– Control of hyperasidity (proton pump inhibitors)

• VIPoma

– Fluid replacement

– Acid- base and electrolyte correction

• Glucagonoma

– Correction of the nutritional status

– Blood transfusion

– Control of hyperglycemia

• Somatostatinoma

– Correction of the nutritional status

– Control of hyperglycemia

Systemic Treatment• Chemotherapy

• Interferon alpha

• Somatostatin analogues

• Radioactive labelled

– Somatostatin analogues

– MIBG

Combination Chemotherapy

• Streptozocin-5-fluorouracil

• Streptozocin-Doxorubicin

• Streptozocin-5-fluorouracil-Doxorubicin

• Cisplatinum-Etoposide

• 5-Fluorouracil-Doxorubicin-Cisplatinum

• 5-fluorouracil-leucovorin-Interferon

Chemoembolisation• Indicated in unresectable liver mets

• May provide symptom and clinical syndrome control

• May result in tumor proliferation control

– Contraindications:

• Liver failure

• Ascites

• Renal failure

• Portal vein obstruction

Biological Treatment• Somatostatin analogues

– Octreotide– Lanreotide– SOM230

• Interferon– Interferon alfa-2a (Roferon-A)– Interferon alfa-2b (Intron A)

INTERFERON TREATMENT:Controversies:

• No concensus on the dose and regimen to be used

• No randomized trial showing improvenment of survival with interferon

SOMATOSTATIN ANALOGUES• Octreotide – Sandostatin

• Lanreotid-

• Somatuline-BIM 230146

• SOM230

• Octastatin- RC-160• Somatostatin analogues are used in the treatment of carcinoid

tumors and functional islet cell tumors of the pancreas

OCTREOTIDE FOR TREATMENT OF NET

• Somatostatin analogues provide:

– Symptomatic response : % 70

– Biochemical response : % 30-50

– Tumor control : % 3

Di Bartolomeo,

Cancer, 1996.

TUMOR TARGETED RADIOACTIVE TREATMENT

MIBG - META-IODOBENZYLGUANIDINE

• Is an catecolamine analog used in localization of adrenal medulla and nonmeduller NET

• 123I labelled MIBG is used for diagnostic purposes

• Kaltas et al, J Clin Endocrinol Metab, 2001

– 12 pts

– 11/12 111In-pentetreotide positive

– 1/12’si 123I-MIBG (+)

– 123I-MIBG may be done to select patients for 131I-MIBG radionuclide therapy

TUMOR TARGETED RADIOACTIVE SOMATOSTATIN TREATMENT

• Alpha-emitting radioligands

– Short acting auger electrons are used

111 In-pentetreotide

• Beta-emitting radioligands

– High energy beta particules

– 90Y-DOTA0 Tyr3-octreotide (OctreoTher)

– 177Lu-DOTA0 Tyr3-octreotate

– 90Y-lanreotide

– Can only be used in sst2 and sst5 (+) NET

de Herder et al, Curr Opin Oncol, 2002

Bortezomib(PS-341): May increase progression free survival

Endostatin

Thalidomide

Bevacizumab: Increased progression free survival, however biochemical control was better in the interferon arm

ImatinibPFS survival was significantly better in patients with concurrent octreotite

SU11248 showed clinical activity in NETs

Gefinitib Produced prolonged disease stabilization

TemsirolismusStabilization of diesase was observed in patients with progressive diease under various medical treatments.

Multiple Endocrine Neoplasia

• MEN 1– Pituitary adenoma– Pancreatic endocrine tumor– Parathyroid neoplasia (90%)

• MEN 2a– Medullary thyroid cancer (100%)– Pheochromocytoma (50%)– Parathyroid neoplasia (10-40%)

• MEN 2b– Medullary thyroid cancer (100%)– Pheochromocytoma (50%)– Neuromas (100%)

Multiple Endocrine Neoplasia Type 1

• Primary hyperparathyroidism 90%

• Pituitary tumours 20-40% (90% at autopsy)

• Pancreatic endocrine tumours 30-70%; (carcinoid 10%)

• Chromosome identified 11q13 (LOH)

• MEN-1 gene cloned 1997

• Makes protein MENIN which affects speed of cell

growth/replication

Von Hippel Lindau• phaeochromocytoma, retinal/cerebellar haemangioblastoma,

renal and pancreatic tumours, middle ear tumours

• pancreatic NETs 15-20% - especially non-functional and PP, SST positive tumours

• chromosome 3 short arm

• VHL protein involved in regulation of cell replication

• NETs also described in Recklinghausen disease, Tuberous Sclerosis