Gastrointestinal and pancreatic neuroendocrine tumours - - PowerPoint PPT Presentation

Gastrointestinal and pancreatic neuroendocrine tumours

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Oberndorfer first described and depicted carcinoid tumors in 1907

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Incidence GEP-NETs? 5/100.000 Epidemiology

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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)

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increase in reported annual age-adjusted incidence from 1973 (1.09/100,000) to 2004 (5.25/100,000 5

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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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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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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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How can GI neuroendocrine tumors be classified?

• Embryological origin/Localisation.
• Histopathological features
• Clinical features

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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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11 James C. Yao, 2008, Journal of clinical oncology

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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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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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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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Clinical features How can you characterize NETs according to their clinical features?

• Functioning vs. non-functioning

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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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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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Carcinoid Carcinoid is still in common usage (historical)  well- differentiated serotonin (5-hydroxytryptamine)-secreting midgut tumour (jejunum, ileum)

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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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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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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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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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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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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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Biochemistry

Peptide markers specific to the tumour site

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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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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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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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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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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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Secretin test:

• Paradox gastin increase of 120pg/ml after i.v. secretin (2IE/kg) after 30

minutes.

• Sensitivitity/specificity > 90 %

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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

• ften

Surgical removal with lymphnodes Variabel

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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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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
• r 68Ga-labelled peptide PET/CT imaging positively predicts response

to somatostatin analogue therapy

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Treatment

How would you treat NETs in general?

• Resection if possible … only curative treatment

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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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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
• r metastatic), progressive well-differentiated pancreatic

NETs

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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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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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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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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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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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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