Gastrointestinal and pancreatic neuroendocrine tumours
Gastroenterologie Oberndorfer first described and depicted carcinoid tumors in 1907 2 Titel der Präsentation / Name Referent/-in 2
Gastroenterologie Epidemiology Incidence GEP-NETs? 5/100.000 Titel der Präsentation / Name Referent/-in 3
Incidence rates of gastroenteropancreatic neuroendocrine tumours (n/100 Gastroenterologie 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 Titel der Präsentation / Name Referent/-in 4
Gastroenterologie increase in reported annual age-adjusted incidence from 1973 (1.09/100,000) to 2004 (5.25/100,000 5 Titel der Präsentation / Name Referent/-in 5
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 Titel der Präsentation / Name Referent/-in 6
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 Titel der Präsentation / Name Referent/-in 7
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 Titel der Präsentation / Name Referent/-in 8
Gastroenterologie How can GI neuroendocrine tumors be classified? • Embryological origin/Localisation . • Histopathological features • Clinical features Titel der Präsentation / Name Referent/-in 9
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 Titel der Präsentation / Name Referent/-in 10
Gastroenterologie James C. Yao, 2008, Journal of clinical oncology 11 Titel der Präsentation / Name Referent/-in 11
Gastroenterologie 12 Titel der Präsentation / Name Referent/-in 12
Gastroenterologie 13 Titel der Präsentation / Name Referent/-in 13
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) Titel der Präsentation / Name Referent/-in 14
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? 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 G3 > 20 > 20 (small or large cell type, MANEC) • 5-year survival rates for grades 1, 2 and 3 tumours are 96%, 73% and 28% Titel der Präsentation / Name Referent/-in 15
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 Titel der Präsentation / Name Referent/-in 16
Gastroenterologie Clinical features How can you characterize NETs according to their clinical features? • Functioning vs. non-functioning Titel der Präsentation / Name Referent/-in 17
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 Titel der Präsentation / Name Referent/-in 18
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) Delay of Gastrinoma Zollinger-Ellison-Syndrome (Diarrhoea, severe peptic diagnosis after Ulceration) symptom onset VIPoma Verner-Morrison Syndrom (profuse watery diarrhoea, 7 years hypokaliaemia, Achorhydriea) Glucagonoma Necrolytic migratory erythema, weight loss, diabetes mellitus, stomatitis, thrombosis, depression, diarrhoea Somatiostatinoma Cholelithiasis, Steatorrhoe Titel der Präsentation / Name Referent/-in 19
Gastroenterologie Carcinoid Carcinoid is still in common usage (historical) well- differentiated serotonin (5-hydroxytryptamine)-secreting midgut tumour (jejunum, ileum) Titel der Präsentation / Name Referent/-in 20
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 Titel der Präsentation / Name Referent/-in 21
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. : Titel der Präsentation / Name Referent/-in 22
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 : Titel der Präsentation / Name Referent/-in 23
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) Titel der Präsentation / Name Referent/-in 24
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 Titel der Präsentation / Name Referent/-in 25
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 … Titel der Präsentation / Name Referent/-in 26
Gastroenterologie Biochemistry Peptide markers specific to the tumour site Titel der Präsentation / Name Referent/-in 27
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%) Titel der Präsentation / Name Referent/-in 28
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 Titel der Präsentation / Name Referent/-in 29
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