Diagnosis and treatment of neuroendocrine tumors
Dan Granberg
Neuroendocrine tumors• Carcinoids
– Bronchial– Thymic– Gastric– Duodenal– Small bowel– Appendiceal– Large bowel– Rectal
• Endocrine pancreatic tumors– Gastrinomas– Insulinomas– Glucagonomas– VIPomas– Somatostatinomas– Non-functioning– Mixed
Diagnosis• Biochemistry• Radiology
–CT –MRI–Ultrasonography –Endoscopic ultrasonography
• Somatostatin receptor scintigraphy = octreoscan• Positron emission tomography = PET• Biopsy• Echocardiography• Endoscopy
Histopathology – Tumour biology
• Neuroendocrine markers
– Chromogranin A
– Synaptophysin
• Specific markers – gastrin, serotonin
• Proliferation marker – Ki-67, PCNA
• Adhesion molecules – CD44
• Angiogenic factors – VEGF, bFGF, TGF• Tyrosine kinase receptors
• Somatostatin receptors – SSTR 1-5
Biochemistry• 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
BiochemistryP-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
Plasma chromogranin A Spontaneous variation
Patients:
• Midgut carcinoid 21
• Sporadic EPT 12
• MEN1 with EPT 7
• Healthy subjects 8
• Total 48
Plasma chromogranin A measured on 2 consecutive days
Granberg 1999
Plasma chromogranin A Spontaneous variation
Results:
Diagnosis n Mean variation
Tumor patients 40 29% (0–113.5%)
Elevated CgA 37 29.5% (0–113.5%)
Normal CgA 3 27% (9–39%)
Healthy subjects 8 21% (0–47%)
Granberg 1999
Plasma chromogranin A Spontaneous variation
Granberg 1999
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
64 patients with GE-NETsExamined by CT, MRI and SRSIn 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 methoddivided 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
CT in neuroendolrine tumors
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%
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%
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
Diagnosis
What information does somatostatin receptor scintigraphy provide?• Finding occult tumors• Staging• Surgery• Medical treatment• Radiotherapy
Diagnosis
What information does somatostatin receptor scintigraphy provide?
Surgery• Guidance: Depicts accessible lesions
for extirpation
Guidance in surgery
Intrathoracic metastases of carcinoid
after 1st operation ….
after 2nd operation…after 2nd operation…
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!)
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
Diagnostic problems
• Small tumors• Staging• Grade of malignancy and tumor biology• Early detection of residual disease or recurrence• Treatment effects
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
Positron emission tomography (PET)
PET• 18FDG
• 11C-methionine
• 11C-L-DOPA
• 18F-DOPA
• 11C-5-Hydroxytryptophane (5-HTP)
• 11C-Hydroxyephedrine (HED)
• 11C-Metomidate
• 68Ga-DOTATOC
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”
PET
Hoegerle 2001
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
PET
PET
Conclusions:
1. Whole-body PET with 11C-5-HTP can detect more tumors than CT and Octreoscan; staging
2. 11C-5-HTP can be used in all types of neuroendocrine tumors: general tracer
3. Of value to find small primary tumors, detect residual disease or recurrence
4. FDG-PET in poorly differentiated tumors
Örlefors 2005
11C-5-HTP-PET of a patient with elevated gastrin levels showing a duodenal gastrinoma not detected by other methods
68Ga-DOTATOC PETPatients, 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
• CTGabriel 2007
68Ga-DOTATOC PETResults:
Gabriel 2007
PET SPECT CT
Sensitivity 97% (69/71) 52% (37/71) 61% (41/67
Specificity 92% (12/13) 92% (12/13) 71% (12/17)
Accuracy 96% (81/84) 58% (49/84) 63% (53/84)
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%)
68Ga-DOTATOC PETConclusions:
• 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
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
PET– Conclusion
Treatment
• Surgery• Liver embolization–Particles–Chemoembolization–SIRT
• Radiofrequency ablation• Biotherapy–Interferon-–Somatostatin analogs
• Chemotherapy• Targeted irradiation therapy