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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)