gastrointestinal and pancreatic neuroendocrine tumours€¢impaired liver and kidney function ......
TRANSCRIPT
Gastrointestinal and pancreatic neuroendocrine
tumours
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Gastroenterologie
Oberndorfer first described and depicted
carcinoid tumors in 1907
2
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Gastroenterologie
Incidence GEP-NETs?
5/100.000
Epidemiology
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Gastroenterologie Incidence rates of gastroenteropancreatic neuroendocrine tumours (n/100
000 per year); age-adjusted using the World standard population
comparing the recent data with Sweden (Hemminki & Li 2001) and
Switzerland (Levi et al. 2000)
4
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Gastroenterologie
increase in reported annual age-adjusted incidence from
1973 (1.09/100,000) to 2004 (5.25/100,000
5
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Gastroenterologie
Genetics
NETs are mainly sporadic, but may occur as part of a complex
familial endocrine cancer syndrome.
Which syndromes are these?
• MEN1, MEN2
• Neurofibromatosis type 1
• Von Hippel Lindau
• Tuberous sclerosis complex
-> detailed family history, clinical examination Genetic
counseling
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Gastroenterologie
MEN 1 + 2
• Autosomal dominant
• > 2 typical tumours, positive familiy history, relatives with
known MEN-mutation
MEN 1
• Mutation tumour-suppressor-gen MEN1 (menin)
• Which tumours/associations?
– Parathyroid hyperplasia (98%)
– Islet cell tumours of pancreas
– Pituitary adenomas and
– Rarer lung and thymus carcinoids
– Frequently type 2 gastric carcinoid in case of gastrinoma
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Gastroenterologie
MEN 2
• Mutation RET protooncogen
• 98 % of MEN 2 patients have? Medullary thyroid cancer
• Which tumours/associations?
MEN 2A
–Medullary thyroid cancer
–Pheochromocytoma
–Parathyroidadenoma/hyperplasia
–Hirschsprungs disease
MEN2B
–Medullary thyroid cancer
–Mucosal neuromas or intestinal ganglioneuromas
–Pheochromocytoma
–„Marfanoid“ body habitus, ectopic lenses
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Gastroenterologie
How can GI neuroendocrine tumors be classified?
• Embryological origin/Localisation.
• Histopathological features
• Clinical features
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Gastroenterologie
How can GI neuroendocrine tumors be classified?
Embryological origin/Localisation.
• Historically NETs were classified according to their
embryological origin, into tumours of the
– foregut (bronchi,stomach, pancreas, gallbladder,
duodenum… till ligamentum of treitz)
–midgut (jejunum, ileum, appendix, right colon) and
–hindgut (distal of right flecture, left colon, rectum)
Prognostic value
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Gastroenterologie
11 James C. Yao, 2008, Journal of clinical oncology
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Gastroenterologie
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Gastroenterologie
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Gastroenterologie
Classification and Characterisation of NETs
NETs are characterised of localisation, stade and histologic criteria
Grading according to WHO 2010
NEN (NET, NEC), all have malignant potential
Staging according to site-specific TNM of ENETs or UICC TNM 7th
edition
T depends on size, esp. For pNETs (SEER database)
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Gastroenterologie
WHO classification 2010 Grading
• To which two major groups are GI neuroendocrine tumours
classified according to WHO 2010 guidelines?
• Which pathomorphologic parameters of the tumours are
used for grading?
• 5-year survival rates for grades 1, 2 and 3 tumours are
96%, 73% and 28%
Differenzierung Grading Mitotic rate: Mitosen/10 HPF Ki-67 Index %
Well-differentiated NET G1 < 2 < 3
Well-differentiated NET G2 2-20 3-20
Poorly-differentiated = NEC
(small or large cell type,
MANEC)
G3 > 20 > 20
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Gastroenterologie
Classification and Characterisation of NETs
•Immunhistochemistry of the
neuroendocrine markers Chromogranin
A und Synaptophysin can help to
establish the neuroendocrine
differenciation
• Detection of the somatostatin receptor
is esp.useful for therapeutic options
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Gastroenterologie
Clinical features
How can you characterize NETs according to their clinical features?
• Functioning vs. non-functioning
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Gastroenterologie
Non-functioning GI neuroendocrine tumors
Which are the typical symptoms of non-functioning NETs?
• Symptoms from pancreatic mass and/or liver metastases
• Pain, nausea and vomiting
• Anaemia due to intestinal blood loss
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Gastroenterologie
Functioning GI neuroendocrine tumors
Which are the typical symptoms of functioning NETs?
Functioning NETs Clinical features
Insulinoma Whipple Trias (hypoglycamic symptoms: confusion, sweating,
dizziness, relief with eating, Hypoglycaemia)
Gastrinoma Zollinger-Ellison-Syndrome (Diarrhoea, severe peptic
Ulceration)
VIPoma Verner-Morrison Syndrom (profuse watery diarrhoea,
hypokaliaemia, Achorhydriea)
Glucagonoma Necrolytic migratory erythema, weight loss, diabetes mellitus,
stomatitis, thrombosis, depression, diarrhoea
Somatiostatinoma Cholelithiasis, Steatorrhoe
Delay of
diagnosis after
symptom onset
7 years
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Gastroenterologie
Carcinoid
Carcinoid is still in common usage (historical) well-
differentiated serotonin (5-hydroxytryptamine)-secreting
midgut tumour (jejunum, ileum)
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Gastroenterologie
Carcinoid syndrome
Typical symptoms?
• Dry flushing +/- palpitations 70 %
• Diarrhoea 50 %
• Intermittend abdominal pain 40 %
• Wheezing
+ possible carcinoid heart disease
Typical symptoms of carcinoid crisis?
• Profound flushing, bronchospasm, tachycardia and
fluctuating blood pressure
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Gastroenterologie
Carcinoid heart disease (CHD)
:
Clinical features?
•Restrictive cardiomyopathy mostly with right-sided valvular
lesions
What is the prevalence of CHD among patients with carcinoid
syndrome at diagnosis?
•20 %
All patients with midgut NETs, with or without hepatic metastasis,
and all patients with the carcinoid syndrome, should be screened
for CHD.
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Gastroenterologie
Carcinoid heart disease (CHD)
:
How could you screen for CHD?
•N-terminal pro-brain natriuretic peptide (NT-proBNP >260 pg/ml
(>30 pmol/l) ) +/- echocardiography.
What is the most important clinical aspect of CHD?
• Dramatic worsening of prognosis
• 3 year survical 31 % vs 68 % without CHD
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Gastroenterologie
Diagnosis
Diagnosis of NETs is based on the followings:
• Pathology gold standard
• Clinical manifestations
• Peptide and amine sectretion
• Radiological and nuclear imaging (Primary tumour, extension)
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Gastroenterologie
Biochemistry
• To assist with initial diagnosis
• To assess the efficacy of treatment
• To assess changing prognosis
• Absence of a marker does not equate to the absence of a tumour
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Gastroenterologie
Biochemistry
Which marker can be used?
• Chromogranin A (general marker)
• Pancreatic polypeptide (can be positive when Chromogranin is negative)
PP may also be a helpful marker in diagnosing which type of NET?
– Non-functioning NETs of the pancreas
• 5-HIAA (serotonin producing tumours)
• Peptide markers specific to the tumour site…
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Gastroenterologie
Biochemistry
Peptide markers specific to the tumour site
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Gastroenterologie
Diagnosis
If the 24 h urine collection of 5’-hydroxyindolaecetic acid (5’-HIAA) is
positive, the most probable and second most probable site site of
tumour is?
• Midgut (jejunum, ileum, proximal colon and appendix (>70%) )
• Stomach and respiratory system (10-35%)
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Gastroenterologie
Diagnosis
What are confounding conditions for the detection of chromogranin A?
• PPI (stop 1-2 weeks bevor measurement)
• Impaired liver and kidney function
How does the patient has to be instructed for the 5-HIAA 24 h urin
collection?
• 48 h – 72 h before dietary and drug restrictions:
• 48 h before no avokados, bananas, eggplant, cantaloupe, pineapple,
plums, tomatoes, kiwi, hickory nuts, dates, grapefruit, walnuts
• Avoid coffee, nicotine and alcohol
• False high values with Paracetamol, Cumarine, Phenobarbital,
diazepam; false low values with Aspirin, Chlorpromazin, Isoniazid,
Levodopa, Streptozotocin
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Gastroenterologie
Diagnosis Gastrinoma (Zollinger-Ellison Syndrom)
Gastrinoma (Zollinger-Ellison Syndrom)
• Acid hypersecretion in the presence of hypergastrinemia
• 25% of the patients have MEN I
• Mostly located in the duodenum (>50%) and pancreas
Diagnostic:
• Gastroscopy (> 50 % duodenal) and histology
• Basal gastrin level (Norm 13 -115 pg/ml, patient has to be fasting > 8 h,
PPI stopp for minimal 1 week, H2 antagonists are
possible/recommended)
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Gastroenterologie
Diagnosis Gastrinoma (Zollinger-Ellison Syndrom)
What are confounding conditions for the detection of Gastrin/
differentialdiagnosis of Hypergastrinaemia?
• Not fasting
• PPI
• Atrophic gastritis, achlorhydria, H. pylori, gastric outlet obstruction,
short-bowel Syndrom, liver or kidney failure
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Gastroenterologie
Diagnosis Gastrinoma (Zollinger-Ellison Syndrom)
In which findings make the diagnosis of a gastrinoma likely?
Gastrin > 1.000 pg/ml + gastric pH > 2 exclusion gastrinoma
Gastrin > 1.000 pg/ml + gastric pH < 2 gastrinoma -tumourlocalisation
Gastrin 110 – 1.000 pg/ml (if gastric pH < 2) secretin test
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Gastroenterologie
Secretin test:
• Paradox gastin increase of 120pg/ml after i.v. secretin (2IE/kg) after 30
minutes.
• Sensitivitity/specificity > 90 %
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Gastroenterologie
Diagnosis
How would you distinguish between different types of NET in the
stomach?
Gastric NET
Number of
tumours
Tumour size
ECL
hyperplasia
Gastrin
Association
Typ I
Solitary or multiple
small
yes
Hypergastrinaemia
autoimmune atrophic
gastritis
Typ II
Solitary or multiple
small
yes
Hypergastrinämie
MEN I, Zollinger-Ellison-
Syndrom
Typ III
Solitary
Often large, > 2 cm
absent
no
Sporadic tumours
Metastasis
Therapy
Prognosis
rare
< 1cm endoscopic removal,
> 2 cm operative removal
Very well
< 1cm endoscopic removal,
> 2 cm operative removal
Very well
often
Surgical removal with
lymphnodes
Variabel
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Gastroenterologie
Diagnosis
Which imaging would you use for the primary tumour
detection/assessing extend of disease for gastrointestinal
and pancreatic NET?
• Imaging: CT/MRI and
• SSRS (somatostatin receptor scintigraphy for detecting
primary tumor)
• EUS (+/- KM), endoscopy
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Gastroenterologie
Diagnosis
Which imaging would you use for assessing the extent of the disease
with/without known primary tumour site?
• Gallium-68 (68Ga) positron emission tomography (PET)/CT is
recommended for the detection of an unknown primary (most
sensitive)
– DOTATOC; DOTATATE; DOTANOC
• In case of poorly differentiated NET, fluorodeoxyglucose (18F-FDG)
PET/CT may be helpful for staging
• The demonstration of somatostatin receptor status by 111In-octreotide
or 68Ga-labelled peptide PET/CT imaging positively predicts response
to somatostatin analogue therapy
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Gastroenterologie
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Gastroenterologie
Treatment
How would you treat NETs in general?
• Resection if possible … only curative treatment
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Gastroenterologie
Treatment early NETs of stomach, duodenum, rectum?
• Small (≤ 1 cm), G1 NETs of the stomach, duodenum or
rectum that do not infiltrate the muscularis propria and do
not show angio-invasion have a very low risk of metastatic
spread (early NETs) Treatment of choice is endoscopic
resection
• All the other intestinal NENs optimal treatment generally
needs surgery and/or medical therapy depending on type,
biology and stage of the tumor, as well as the individual
situation of the patient (curative, also resectable liver
metastasis or palliation with debulking)
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Gastroenterologie
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Gastroenterologie
Treatment
Non-resectable disease: symptom relief
• Somatostatin analogues
• Biotherapy
• Targeted radionuclide therapy
• Locoregional treatments including ablation and (chemo)
embolisation
• Chemotherapy
• Chemotherapy may be used for poorly differentiated NETs,
aggressive Course
• Sunitinib or everolimus may be used advanced (inoperable
or metastatic), progressive well-differentiated pancreatic
NETs
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Gastroenterologie
Treatment
Somatostatin analogues are gold standard in the long-term
medical treatment of NETs.
Which effect do they have on NETs/Indications?
• Biochemical response rates (inhibition of hormone
production) Indication symptomatic treatment
• Antiproliferative Indication progressive disease
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Gastroenterologie
Treatment
How would you avoid and treat carcinoid crisis?
Avoid:
• constant intravenous infusion at a dose of 50 ug per hour,
initiated 12 h before, and given for 24- 48 h after surgical
intervention
Treat:
• bolus intravenous doses of 100-500 ug octreotide
• followed by continuous infusion (50 ug/h)
• Antihistamines and corticosteroids
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Gastroenterologie
Treatment
Why is prophylactic cholecystectomy is recommended ín patients who already receiving, or are due to start long-term treatment with somatostatin analogues?
• Risk of cholelithiasis (10-50%)
Other side effects of somatostatin treatment?
• Local reactions (pain and erythema) at the injection site
• Abdominal cramps, nausea, flatulence, diarrhoea and steatorrhoea
• Bradycardia
• Octreotid LAR 30 mg1/month 2189.80 CHF
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Gastroenterologie
Treatment
Which are the indications for targeted radionuclide therapy?
• inoperable or symptomatic NETs, palliation after maximal medical therapy
and tumour progression
Inclusion criteria for radionuclide therapy?
• superior radiopharmaceutical uptake at all known tumour sites on
diagnostic imaging by comparison with normal tissues
Significant response rates can be achieved with the systemic targeted
radionuclide therapies
• 131I-mIBG 40 - 60 %
• 90Y-DOTATOC and 90YDOTATATE 33- 77 %
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Gastroenterologie
Treatment
Other therapeutic modalities in GI NETs
• Biotherapy
• Interferone alpha
• Targeted radionuclide therapy
• Locoregional treatments including ablation and (chemo) embolisation
• Chemotherapy may be used for poorly differentiated NETs, aggressive
Course (streptozotocin, temozolomide, …)
• Sunitinib or everolimus may be used advanced (inoperable or
metastatic), progressive well-differentiated pancreatic NETs
• Patients with end-stage NETand uncontrollable symptoms OLT (5 y
disease free survival 46 %)
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Gastroenterologie
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Gastroenterologie
Follow-up
Which imaging method and how often would you use for follow-up?
• SSRS imaging is recommended for tumours known to be SSTR-
positive, supplemented by CT and MRI
• Initially 3-6-month intervals, increased to 9-12 months