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Diagnosis and treatment of neuroendocrine tumors

Diagnosis and treatment of neuroendocrine tumors. Dan Granberg. Carcinoids Bronchial Thymic Gastric Duodenal Small bowel Appendiceal Large bowel Rectal. Endocrine pancreatic tumors Gastrinomas Insulinomas Glucagonomas VIPomas Somatostatinomas Non-functioning Mixed.

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Diagnosis and treatment of neuroendocrine tumors

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  1. Diagnosis and treatment of neuroendocrine tumors Dan Granberg

  2. Carcinoids Bronchial Thymic Gastric Duodenal Small bowel Appendiceal Large bowel Rectal Endocrine pancreatic tumors Gastrinomas Insulinomas Glucagonomas VIPomas Somatostatinomas Non-functioning Mixed Neuroendocrine tumors

  3. Diagnosis • Biochemistry • Radiology • CT • MRI • Ultrasonography • Endoscopic ultrasonography • Somatostatin receptor scintigraphy = octreoscan • Positron emission tomography = PET • Biopsy • Echocardiography • Endoscopy

  4. Histopathology – Tumour biology • Neuroendocrine markers • Chromogranin A • Synaptophysin • Specific markers – gastrin, serotonin • Proliferation marker – Ki-67, PCNA • Adhesion molecules – CD44 • Angiogenic factors – VEGF, bFGF, TGFa • Tyrosine kinase receptors • Somatostatin receptors – SSTR 1-5

  5. P-chromogranin A (P-chromogranin B) U-5’HIAA U-MeImAA P-ACTH U-cortisol S-gastrin S-PP (pancreatic polypeptide) P-glucagon P-VIP S-calcitonin S-insulin S-proinsulin S-C-peptide Secretin test Gastric pH 72-hour fasting Meal stimulation test Biochemistry

  6. Biochemistry P-chromogranin A: • Most sensitive marker • Early detection of recurrence (Welin et al) • Treatment monitoring • Pitfalls • Impaired renal function • Treatment with proton pump inhibitors • Chronic atrophic gastritis • Inflammatory bowel disease • Decreased liver function • High spontaneous variation

  7. Plasma chromogranin ASpontaneous variation Patients: Plasma chromogranin A measured on 2 consecutive days Granberg 1999

  8. Plasma chromogranin ASpontaneous variation Results: Granberg 1999

  9. Plasma chromogranin ASpontaneous variation Granberg 1999

  10. Radiology • CT scan • native • i.v. contrast enhancement • late arterial phase = portal venous phase • venous phase • MRI • Ultrasonography • biopsy • Endoscopic ultrasonography • Intaoperative ultrasonography • Echocardiography • carcinoid heart disease

  11. CT in neuroendolrine tumors 64 patients with GE-NETs Examined by CT, MRI and SRS In 40 pats (62,5%) liver metastases were found Maximum number of lesions detected for each patient (by SRS or CT or MRI) were added = Total number Relative sensitivity = number of lesions detected by method divided by total number of lesions. In a lesion-by-lesion analysis the sensitivities were: SRS 49% (204 mets) CT 79% (325 mets) MRI 95% (394 mets) Dromain 2005

  12. Somatostatin receptor scintigraphy Neuroendocrine tumors: • Carcinoids • Midgut >90% • Bronchial 67% • Endocrine pancreatic tumors • Gastrinomas >90% • Insulinomas <50% • Paragangliomas >90% • Pheocromocytomas 86% • Neuroblastomas 90% • Medullary thyroid carcinomas 65%

  13. Somatostatin receptor scintigraphy Other malignancies: • Small cell lung cancer 100% • Non small cell lung cancer 100% • Malignant lymphoma • Hodgkin’s diease >95% • Non-Hodgkin’s lymphoma 80% • Meningeoma 100% • Thyroid cancer 80% • Pituitary tumors 70-75% • Astrocytoma 65% • Breast cancer 65%

  14. Somatostatin receptor scintigraphy Non-malignant diseases: • Sarcoidosis 100% • Wegener’s granulomatosis 100% • Tuberculosis 65% • Grave’s disease • Rheumatoid arthritis 100% • Sjögren’s syndrome 80% • Pneumonia

  15. Diagnosis What information does somatostatin receptor scintigraphy provide? • Finding occult tumors • Staging • Surgery • Medical treatment • Radiotherapy

  16. Diagnosis What information does somatostatin receptor scintigraphy provide? Surgery • Guidance: Depicts accessible lesions for extirpation

  17. Guidance in surgery

  18. Intrathoracic metastases of carcinoid

  19. after 1st operation ….

  20. after 2nd operation…

  21. Diagnosis What information does somatostatin receptor scintigraphy provide? Medical treatment • Grade of uptake in the tumor allows prediction of value of treatment with Somatostatin analogues (cost effectiveness!)

  22. Diagnosis What information does somatostatin receptor scintigraphy provide? Radiotherapy • Might depict field of external beam irradiation • Grade of uptake: determines feasibility of receptor guided isotope treatment • Dosimetry

  23. Diagnostic problems • Small tumors • Staging • Grade of malignancy and tumor biology • Early detection of residual disease or recurrence • Treatment effects

  24. Positron emission tomography (PET) • Is a technique for • in vivo tracer studies • labeled with radionuclides (11C, 18F, 15O, 68Ga) • biologically unchanged molecules • images a physiological principle (receptor binding, metabolism, tissue perfusion, blood flow etc) • FDG-PET (18fluorodeoxyglucose) images glucose transport

  25. PET • 18FDG • 11C-methionine • 11C-L-DOPA • 18F-DOPA • 11C-5-Hydroxytryptophane (5-HTP) • 11C-Hydroxyephedrine (HED) • 11C-Metomidate • 68Ga-DOTATOC

  26. PET Whole-Body 18F-DOPA PET for Detection of Gastrointestinal Carcinoid Tumors. Overall sensitivities: 18F-DOPA 65%, FDG-PET 29% Octreoscan 57%, CT/MRI 73% “PET enabled best localization of primary tumors and lymph node metastases” Hoegerle 2001

  27. PET Comparison of PET with 11C-5-HTP, Octreoscan + SPECT and CT • Tumours were imaged by: • PET in 95% (36/38) • SRS in 84% (32/38) • CT in 79% (30/38) • PET could visualise the primary tumour in 84% (16/19), compared to SRS in 58% (11/19) and in CT 47% (9/19) of patients • In 58% PET could detect more lesions than SRS and CT Örlefors 2005

  28. PET Conclusions: • Whole-body PET with 11C-5-HTP can detect more tumors than CT and Octreoscan; staging • 11C-5-HTP can be used in all types of neuroendocrine tumors: general tracer • Of value to find small primary tumors, detect residual disease or recurrence • FDG-PET in poorly differentiated tumors Örlefors 2005

  29. 11C-5-HTP-PET of a patient with elevated gastrin levels showing a duodenal gastrinoma not detected by other methods

  30. 68Ga-DOTATOC PET Patients, n=84 • Diagnosis of suspected NET, n=13 • Staging of histologically proven NET, n=36 • Detection of recurrence after therapy, n=35 • Endocrine symptoms, n=27, non-functioning, n=57 Comparison with: • 111In-DOTATOC-scintigraphy with SPECT, n=33 • n=18 • 99mTc-HYNICTOC-scintigraphy with SPECT, n=33 • CT Gabriel 2007

  31. 68Ga-DOTATOC PET Results: Combination of PET and CT: 100% sensitivity Further clinically relevant information in comparison with: • Diagnostic CT – 18 patients (21.4%) • Scintigraphy – 12 patients (14.3%) Gabriel 2007

  32. 68Ga-DOTATOC PET Conclusions: • PET using 68Ga-DOTATOC yields higher detection rates compared to 111In-octreotide scintigraphy and diagnostic CT with clinical impact in a considerable number of patients • The combination of PET and CT showed the highest accuracy Gabriel 2007

  33. PET– Conclusion Functional imaging of endocrine tumors with PET is promising Pros: Specific tracers for certain tumors provide excellent visualization. Prospective studies are needed to established the diagnostic efficacy and cost-benefit Cons: Lack of availability (11C-5-HTP, 18F, 68Ga) PET/CT will improve morphological localization

  34. Treatment • Surgery • Liver embolization • Particles • Chemoembolization • SIRT • Radiofrequency ablation • Biotherapy • Interferon-a • Somatostatin analogs • Chemotherapy • Targeted irradiation therapy

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