Gastroenteropancreatic neuroendocrine tumors

(GEP – NET)

prof. Marek Bolanowski, Marek Bolanowski, MD, PhD

Department of Endocrinology, Diabetes and Isotope Therapy

ED yr V

Internal diseases, endocrinology

Carcinoid

• Jahrestagung der Deutschen Gesellschaft für

Pathologie, Dresden, 17.09.1907

• Siegfried Oberndorfer (1875-1944)

• Karzinoide – carcinoma-like

Neuroendocrine tumors - NETs

• Heterogenous group of neoplasms deriving from the cells of disseminated neuroendocrine system in various organs.

• APUD (amine precursors uptake and decarboxylation)

• Neuroendocrine tumors originating from GI system, lungs and thymus – traditionally carcinoids.

• Poorly differentiated NETs - very aggressive course.

• Well differentiated NETs - slowly growing.

• Ability to produce and secrete metabolically active substances causing certain clinical symptoms.

• Sporadic / familial syndromes.

Gastroenteropancreatic tumors (GEP - NETs)

Epidemiology

• Incidence: 90 / 1 000 000 / yr

• Prevalence: 200-300 / 1 000 000

• Autopsy: 84 / 1 000 000

• (70% of NETs and 2% of GI neoplasms)

• Each age, peak in 6th decade

• Carcinoids - about 50%

Embryological characteristics of GEP-NETs

• Foregut

(anterior part of the alimentary canal)

respiratory system, thymus,

stomach, duodenum, pancreas

• Midgut

(middle part of the alimentary canal)

small intestine, appendix,

ascending colon

• Hindgut

(posterior part of the alimentary canal)

transverse colon, sigmoideum,

rectum

Foregut

Midgut

Hindgut

Clinical characteristics of GEP-NETs

• Secreting tumors

• hormones, peptides, kinins...

• Non-secreting tumors

• Carcinoids

Clinical characteristics of secreting GEP-NETs

• Insulinoma

• Gastrinoma

• Glucagonoma

• VIP-oma

• Somatostatinoma

• PP-oma

Tumor type, frequency and malignancy

Tumor type Frequency

(%)

Malignancy (%)

Carcinoid 50 90

Insulinoma 15 10

Gastrinoma 5 55

Glucagonoma 2 80

VIP-oma 1 80

Somatostatinoma 1 50

Non-functional ≈ 30 70

Insulinoma

• most common pancreatic islets tumor from beta cells

• insulin secretion in excess

• hypoglycemia

• headache, confusion, visual disturbances, weakness,

sweating, tremor, palpitations, consciousness loss, coma

• weight gain

• fasting test – 72 hrs.

• malignant - rare (10%)

• multifocal (10%)

Gastrinoma

• duodenal or pancreatic tumor

• in 5% atypical location

• gastrin secretion in excess

• gastric acid hypersecretion, recurrent peptic ulcers of

stomach, duodenum or of atypical location, diarrhea

(Zollinger-Ellison syndrome)

• possible ACTH secretion - Cushing’s syndrome

• in 1/3 as a part of MEN-1

• sporadic forms – malignant up to 40-80%

Glucagonoma

• pancreatic islet tumor from alfa cells

• necrolytic migratory erythema, rash and hyperpigmentation

of mouth and genital region (80%)

• often thrombo-embolic episodes

• frank diabetes, glucose intolerance

• depression…

VIP-oma – Verner-Morrison syndrome

• originates from autonomic nervous system cells

• possible localization in pancreas, nervous system or

adrenals

• VIP (vasoactive intestinal polypeptide) secretion

• watery diarrhea, hypokalemia, achlorhydria - WDHA

Somatostatinoma

• from pancreatic islets D cells

• somatostatin (SS) secretion

• women/men 2:1

• fatty stools, fatty diarrhea, cholelithiasis, abdominal pain

• diabetes, hypochlorhydria

• gallbladder functional disturbances, weight loss

PP-oma

• tumor secreting pancreatic polypeptide - PP

• asymptomatic usually

• diarrhea possible

• weight loss

• diabetes rare

Other

• Neurotensinoma hypotension, tachycardia, cyanosis, oedema, vasodilatation,

diabetes

• Ghrelinoma hyperglycemia, insulin deficiency, insulin resistance, GH/IGF-1

excess, acromegaly, gastric acid hypersecretion, intestinal movements disturbances

• ACTH, GRF (GHRH), PTH, CT, LH, MSH

• CGRP, PTHrP,

• EG, CCK, GIP, GRP, NKA

Non-secreting tumors (hormonally inactive)

• non-specific symptoms

abdominal pain

mechanical icterus (jaundice)

motility disturbances

Clinical symptoms of NETs

• flushing episodes 84%

• diarrhea 79%

• valvular heart defects 37%

• bronchospasm 17%

• miopathy 7%

• pigmentation, arthropathy 5%

• hyperglycemia, hypoglycemia, peptic ulcer

disease, rash, exanthema < 1%

Carcinoid

• According to new classification carcinoid

(most common GEP tumor) = serotonin

secreting tumor originating from midgut,

only.

Carcinoid

• Intestine wall, pancreas, appendix, colon, rectum,

stomach, duodenum, lungs, bronchi, ovary, thymus ...

• Often with metastases

• < 1 cm – metastases in 15%

• > 2 cm – metastases in 95%

• Episodic occurrence of symptoms

• 10 years from first symptoms to diagnosis

Carcinoid syndrome symptoms

• in less than 10% patients with carcinoid

• more often in small intestine tumors

Arthritis

(7%)

Skin lesions

(5%)

Diarrhea (68-84%)

Cyanosis

(18%)

Heart lesions

(14-41%)

Flushing (63-94%)

Teleangiectasiae

(25%)

Bronchospasm

(3-19%)

Abdominal pain

(10-55%)

Carcinoid syndrome symptoms site and frequency

Differential diagnostics

• heart failure (dyspnoea)

• pheochromocytoma (skin lesions)

• thyroid medullary carcinoma (diarrhea)

• diabetic neuropathy

• menopause (flush)

• epilepsy

• panic, fear

Laboratory diagnostics

• urinary 5-HIAA excretion

• serum serotonin concentration

• serum chromogranins A, B and C

• CgA – prognostic marker of survival

• CgB – marker of benign insulinoma

• neuron-specific enolase – NSE, synaptophysin, PGP 9.5

• insulin, gastrin, VIP, glucagon levels

• CA-19 - malignancy marker

Histology of GEPs (WHO)

1. Well differentiated neuroendocrine tumor 1A with benign course

1B with benign or potentially malignant course

2. Well differentiated neuroendocrine cancer (low malignancy)

3. Poorly differentiated neuroendocrine cancer (high malignancy)

Imaging

• spiral CT

• MRI

• US (endoscopic) + biopsy

• capsule endoscopy

• double-balloon enteroscopy

• somatostatin receptors scintigraphy (OctreoScan)

• angiography

• PET

Somatostatin receptors scintigraphy

Treatment

Surgery – therapy of choice

• cytoreductive surgery: tumor resection, ablative radiotherapy, cryotherapy

• aims: stop of tumor growth, biochemical normalization, quality of life improvement

Pharmacotherapy

Specific treatment of secreting tumors

Radioisotope therapy

Somatostatin analogs

Anti-neoplastic activity

• Direct (SS receptors)

• Indirect

• growth factors inhibition

• influence on immunological system

• apoptosis induction

• angiogenesis inhibition

Somatostatin analogs

• Clinical improvement in 30-85% of patients

• Decline in level of markers in 50%

• Stabilization of tumor growth in 40-80%

• Tumor regression in 5%

Somatostatin analogs

• Octreotide

Sandostatin (i.v. 2-3 times daily)

Sandostatin LAR 10, 20, 30 mg (i.m. every 28 days)

• Lanreotide

Somatuline LP 30 mg (s.c. every 14 days)

Somatuline Autogel 60, 90, 120 mg (s.c. every 28-56 days)

• Pasireotide

• Vapreotide

Duration of action of somatostatin analogs single dose

Octreotide

Somatuline PR

Octreotide LAR

Somatuline

Autogel

Duration of action (days)

Up to 56 days

for ATG 120 mg

Somatostatin analogs in practice

• Receptors presence

• Hormones-related symptoms

• Origin from foregut and midgut

• Carcinoid syndrome

• VIP-oma, glucagonoma

• Malignant gastrinoma and insulinoma

• GHRH secreting tumors (acromegaly)

Acute therapy (fast and short acting analogs)

Chronic therapy in order to decrease of the symptoms (long-acting

analogs)

Interferon alfa

Anti-neoplastic activity

• Influence on proliferation, differentiation, apoptosis and

angiogenesis

• Metastasis fibrosis induction (liver)

• Control of clinical symptoms and biochemical response

in 46-77%

Possible administration together with

somatostatin analogs

Other therapies

Radioisotope therapy • 125I-MIBG, 131I-MIBG

• 111I-DTPA-octreotide – indium labelled SS analog

• 90Y-DOTA-TOC – radionuclide emiting beta radiation binding to SS receptors type 2 and type 5

Specific therapy of secreting tumors • diazoxide, streptozotocine

• proton pump inhibitors (PPI), histamine receptor antagonists

Effects of 90Y/177Lu DOTA-TATE therapy

Before therapy After therapy

Chemotherapy

• In patients with advanced disease

• Poorly differentiated pancreatic tumors, especially

• Chlorozotocine, streptozotocine, 5-FU, adriamycine, lomustine, doxorubicine

Treatment - perspectives

• Angiogenesis inhibitors – VEGF (vascular endothelium growth factor) and VEGF receptors

• Thyrosine kinase inhibitors – (sunitinib, imatinib, gefinitib)

• Inhibitors of serine-treonine protein kinase mTOR (mammalian target of rapamycin) – immunosuppression, inhibition of proliferation and survival of neoplastic cell (everolimus)

• Monoclonal antibodies (bevacizumab)

• Temozolomide

Unfavorable prognostic factors of GEP-NETs

• Age >50, males

• Site: pancreas, rectum

• Tumor size and penetration depth

• Metastases, radical therapy impossible

• Clinical symptoms

• Carcinoid syndrome symptoms

• High markers (CgA, 5-HIAA, CT, gastrin, ACTH)

• High proliferative index

Multiple endocrine neoplasia

Well-characterized, inherited, plurihormonal disorders

with simultaneous neoplastic transformation and

hyperfunction of several endocrine glands.

• family history, hereditary

• germline DNA testing

• MEN-I (mutation inactivating the menin tumor suppressor on

chromosome 11q13)

• MEN-II a (activating mutation of RET protooncogene on

chromosome 10q11.2)

• MEN-II b (RET mutation at codon 918 – exon 16)

MEN-I

• rare, autosomal dominant condition

• well differentiated, benign tumors

• parathyroid glands

• pancreas (islet tumors)

• pituitary (adenomas)

• duodenum

• adrenal cortex

– bronchial, thymic NETs

– dermal lesions, thyroid disease, meningeal tumors…

MEN-I

• Pituitary 45%

• Skin 75%

• Parathyroids

89%

• Gastrointestinal

system 54%

• Adrenals 18%

MEN-IIa

Neoplastic transformation of:

• parathyroids

• thyroid parafollicular C cells

• adrenal medulla

• hyperparathyroidism

• medullary thyroid carcinoma

• pheochromocytoma

• Increased mortality (mean age 60 yrs)

MEN-IIb

Neoplastic transformation of:

• thyroid parafollicular C cells

• adrenal medulla

• multiple mucosal neuromas

• medullary thyroid carcinoma

• pheochromocytoma

• Marfanoid signs

• High mortality (mean age 30 yrs)

Other disorders with multiple endocrine organs involvement

Carney complex

• cardiac, endocrine, cutaneus and neural tumors

• myxomas (heart, breast, skin), spotty pigmentation of the skin

• primary pigmented micronodular adrenocortical hyperplasia

• pituitary, adrenals, thyroid and testes tumors

Neurofibromatosis type 1 (Recklinghausen disease)

• cafe au lait spots, neurofibromas, gliomas,

• endocrine tumors (pheo, hyperparathyroidism, MTC, carcinoids)

von Hippel-Lindau disease

• hemangioblastomas (retinal, cerebellar)

• renal cell carcinoma, islet cell tumors, pheochromocytoma

• cysts (renal, pancreatic, epidydymal)