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

12

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Gastroenterologie

13

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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