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