Radionuclide Functioning Imaging of Neuroendocrine Tumors (NET)

Hussein Farghaly, MDAssistant Prof. and Consultant of Nuclear Medicine

Assiut University-Egypt 2014

Neuroendocrine tumors• NET are derived from embryonic neural crest tissue found in the

hypothalamus, pituitary gland, thyroid gland, adrenal medulla, and gastrointestinal tract.

• NET´s belong to the so called amine precursor uptake and decarboxylation (APUD)- omas

• Generally more indolent than adenocarcinoma of the same site.

• Capable of producing hormonal syndrome (i.e. carcinoid syndrome)

– WHO classification

• Well differentiated neuroendocrine tumor• Well differentiated neuroendocrine carcinoma• Poorly differentiated neuroendocrine carcinoma

Neuroendocrine tumors most commonly encountered in clinical practice

- Enteropancreatic tumors (carcinoid tumors, gastrinoma, glucagonoma, vasoactive intestinal peptide [VIP]–related tumors [VIPomas]

– Poorly differentiated neuroendocrine tumors

– Sympathoadrenal tumors (pheochromocytoma [PHEO], neuroblastoma, paraganglioma)

– Multiple endocrine neoplasia (MEN) syndromes (type 1 MEN, type 2 MEN)

– Medullary thyroid carcinoma (MTC).

Radiopharmaceuticals• Radiopharmaceuticals used for imaging neuroendocrine tumors are either

similar in molecular structure to the hormones synthesize or incorporated into various metabolic and cellular processes of the tumor cells.

• Somatostatin Analogs (111-In DTPA /99mTc-Octreotide, Ga68-DOTA)

• Catecholamine Analogs and metabolities (131I/123I-MIBG,18F/11C-DOPA, 11C-HTP, 11C-HED)

• Glucose Analog (18F-FDG)

Indication Of NETs Radionuclide Imaging

Somatostatin Analogues• Neuroendocrine tumors (NETs) express multiple somatostatin receptors (SSR1

to SSR5)

• Somatostatin receptor type 2 (SSR2) is clearly predominant.

• These receptors represent the molecular basis for the clinical use of somatostatin analogues in the imaging and treatment of endocrine tumors

• 3 somatostatin analogs, OC, TOC and TATE were conjugated to the metal chelator DOTA and labeled with the radiometal 111In, 90Y and 68Ga.

• Somatostatin receptor scintigraphy (SRS) had been used for the detection of occult primary tumors and metastatic lesions, and it had been suggested that it should be the first imaging procedure for staging, before CT and MRI.

A. Hubalewska-Dydejczyk et al., Eur J Nucl Med Mol Imaging (2006)

Somatostatin and Octreotide:Molecular Characteristics

Amino acids essentialfor receptor binding

ala gly cys lysasnphephe

cys ser thrphethr

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OctreotideHuman somatostatin

Harris AG. Drug Invest. 1992;4(suppl 3):1-54.

Tumors with High Expression of SSR

• 1. Adrenal medullary tumors (pheochromocytoma, neuroblastoma, ganglioneuroma, paraganglioma)

• 2. Gastroenteropancreatic neuroendocrine tumors (formerly termed carcinoid, gastrinoma, glucagonoma, vasoactive intestinal polypeptide-secreting tumor, pancreatic polypeptide- secreting tumor, etc., or nonfunctioning gastroenteropancreatic tumors),

• 3. Merkel cell tumor of the skin

• 4. Pituitary adenoma

• 5. Small-cell lung carcinoma

Tumors with Low Expression of SSR

1.Astrocytoma

2. Benign and malignant bone tumors

3. Breast carcinoma

4. Differentiated thyroid carcinoma (papillary, follicular, Hu¨rthle cell)

5. Lymphoma (Hodgkin and non-Hodgkin)

6. Melanoma

7. Meningioma

8. Non–small cell lung carcinoma

9. Prostate carcinoma

10. Renal cell carcinoma

11. Sarcomas

Tumors with Variable Expression of SSR (especially Subtype 2)

1. Insulinoma

2. Medullary thyroid carcinoma

D. Expression of SSR in Nonneoplastic Processes

1. Autoimmune diseases (e.g., rheumatoid arthritis, Graves’ disease, Graves’ ophthalmopathy)

2. Bacterial pneumonia

3. Cerebrovascular accident

4. Fibrous dysplasia

5. Granulomatous diseases (e.g., tuberculosis, sarcoid)

6. Postradiation inflammation

Oncological and non oncological SSR expression

Radionuclide for Somatostatin receptor ImagingSSR Radiotracer Source Injected

doseImaging time Imaging Dosimetry

In-111-Octreotide In-111-Lanreotide

cyclotron 222 MBq(173 and 247 KeV),

24 P.I(4 and 48 hrs optional) T1/2: 67 h

Planner+ SPECT (SPECT/CT)

12 mSv+Augerelectrons

Tc-99m- OctreotateTc-99m- OctreotideTc-99m- depreotide

Tc-99m generator

740 MBq 2 and 4 (24 hrs optional) P.I T1/2: 6h

Planner+ SPECT (SPECT/CT)

4 mSv

68Ga-DOTANOC; sstr2,3,5 First,

68Ga-DOTATOC,

68Ga-DOTATATE. Recent, sstr2 in 10x

Ge68/Ga68

generator

165–243 MBq (mean 202 MBq)

After 30-to 60-min uptake periodT1/2: 68 minutes

PET/CT 3-4 mSv

Results of the clinical application of somatostatin receptor imaging using various ligands in patients with

gastroenteropancreatic neuroendocrine tumors

Normal distribution in radio labeled SR analog

Causes of potential misinterpretation of results with octreotide scintigraphy

In-111- OCTREOTIDE IMAGING

WHAT IS THE EXPECTED DIAGNOSIS?Paraganglioma PheoCh Neuroblastoma

56 year old female presents with nausea, flushing, and low back pain. No history of hypertension. Blood work revealed elevated levels of norepinehprine, epinephrine dopamine and cathecholamines. ultrasound and CT scan demonstrated a large right suprarenal mass. Plan-obtain octreotide scan to evaluate primary lesion and search for additional lesions.

Right adrenal pheochromocytoma

• 65-year-old male who has poorly differentiated neuroendocrine carcinoma of the liver by biopsy. In-111-Octreotide was obtained to evaluate for additional sites of metastatic disease and for assessment of possible primary site of disease

4 hrs WB images 24 hrs WB imagesIs this a normal octreotide scan?

Teaching pointKnowing normal biodistribution of In-111 octreotide is very important as it was the key in this case.

78 years old male Saudi patient with known carcinoid tumor s/p resection from small bowel, mediastinal lymph nodes and recently elevated tumor markers

– 5HIAA / 24 h urine = 88 μmol/24 h (normal 10.5–47.2 μmol/24 h)

– Serum CEA = 7.2 ug/L (normal 0-3.4 ug/L) Serum CA 19-9 = 55 u/ml (normal 0-34 u/ml)

99mTc-octreotide (Tektrotyd) Scan (1)

– Tc-99m Tektrotyd

Liver lesions-not on CT

Abdominal mesenteric LNs

Lt supraclav. and mediastinal LNs

• 62 year old female patient with carcinoid of small bowel, post resection and anastomosis and elevated tumor markers for assessment.

• 5HIAA / 24 h urine = 70.7 μmol/24 h (normal 10.5–47.2 μmol/24 h)

99mTc-EDDA/HYNIC-octreotide (Tektrotyd) Scan (2)

Patient presented with metastatic left supraclavicular LN from unknown NET with multiple hepatic metastases seen in CT was investigated with SRS.

GASTRINOMA

99mTc-EDDA/HYNIC-octreotide (Tektrotyd) Scan (2)

Shah, et al; Indian Journal of Radiology and Imaging November 2011.

SPECT/CT improves image interpretation

• Identify unsuspected tumor or extent of ca

• Differentiate physiologic activity from ca

• Significant Change in Management

A metastatic case of small bowel NET treated by Peptide Receptor Radionuclide Therapy (PRRT). T-99m SSR Imaging ordered to assess response to therapy.

A) the baseline planar WB image shows uptake in the primary (thin arrow) and multiple hepatic metastasis (thick arrow). (B)WB planar SSTR imaging after 3 cycles of SS therapy show complete regression of the tracer uptake at the primary and the hepatic metastasis indicating the suppression of SSR due to therapy.

The patient considered responder and completed further therapy. He was documented to be DF on his last follow-up, 1.5 year post last radioimmunoscintigraphy.

Shah, et al; Indian Journal of Radiology and Imaging November 2011.

68Ga-DOTA-TOC PET/CT

A case of tail of Pancreas NET with only metastatic hepatic lesions seen US, CT and MRI.

With a permission from Abdullah ALQARNI PSMMC NucMed symposium 2013,

A 55-y-old woman with multiple small liver metastases from pancreatic head NET S/P surgical resection and received 4 cycles of 177Lu-DOTA-TATE

68Ga-DOTATOC PET scan (A) Before SRRT showed multiple small hepatic metastasis.

(B) Post therapy scan showed excellent treatment response .

(C and D) However, corresponding CT scans initiallyshowed no remarkable change in liver lesions

68Ga-DOTATOC PET scan in treatment monitoring

Gabrie et al; J Nucl Med 2009; 50:1427–1434

Baum et al; SNM 2008

Middle age woman with longstandinghistory of ‘chronic pancreatitis’. At second operation found to have subcentimetre hepatic metastasis with histology demonstrating well-differentiated neuroendocrine tumour.

Triple phase CT scan demonstrated no abnormality apart from multiple sclerotic bone lesions considered to be benign bony islands (osteopoikylosis) with prior ‘negative’ bone biopsy.

GaTate positron emission tomography (PET)/CT scan (MIP) and selected axial PET/CT fusion slices) performed 1 week later demonstrated a pancreatic primary and sub-centimetre liver metastasis (red arrows), and widespread nodal and osseous metastases.

The patient subsequently underwent radionuclidetherapy with 177lutetium-octreotate.

MS Hofman et al. J of Medical Imaging and Rad Onco © 2012

111In-octreotide scan anterior planar and single photon emission tomography/CT (not shown) demonstrated a solitary left supraclavicular nodal abnormality (blue arrow).

111In-octreotide scan 68 Ga-DOTATATE

Baum et al; SNM 2008

• MIBG shows the same cellular transport system as norepinephrine, and accumulates in neuroendocrine tumors, mainly in pheochromocytoma, neuroblastoma, and paraganglioma.

• MIBG scintigraphy has a limited role in the management of carcinoids and in GEP tumors, while it has found a large application for the diagnosis of neoplasia of sympathoadrenal lineage

• 60–70% of carcinoids are visualized using MIBG

I-131/I-123 Metaiodobenzylguanidine (MIBG)

ANT. POST.

Normal MIBG uptake

50-year-old man with a palpable neck mass, progressive dyspnea, and intermittent episodes of supraventricular tachycardia. Abdominal CT revealed only a 2-cm left adrenal nodule, which was thought to be an incidental finding.

(a) Anterior whole-body In-111 pentetreotide image shows the neck mass (arrow) and anterior mediastinal uptake (arrowhead).

(b, c) Anterior I-131 MIBG scans of the head (b) and chest (c) show the neck mass (white arrow in b), mediastinal uptake(black arrow in b and c), and a faint focus inferior to the mass (arrowhead). No abnormal uptake was seen in the abdomenand pelvis, including the suprarenal area.

Carotid body paraganglioma (glomus tumor)

At surgery, the neck mass proved to be a paraganglioma at the carotid bifurcation, with a small satellite lesion adjacent to the trachea corresponding to the faint focus. Mediastinal uptake on all three images represented normal thymic tissue.

Intenzo et al; RadioGraphics 2007

Teaching pointsParaganglioma is both MIBG and SR avid lesion.

-Paraganglioma lighten up more in MIBG than in SRS with more lesions seen in MIBG.

Normal thymic tissue can be MIBG and SR positive

What is the differential diagnosis?

A case 8-month-old girl who was admitted for URI symptoms. At that time, a right upper quadrant mass was detected on physical examination

CT Findings: There is a large, heterogeneously enhancing mass within the right mid and upper abdomen, with several regions of calcification within this mass.

Bone Scan: There is uptake of Tc-99m MDP in the CT noted abdominal mass, which extends to the midline

I-123 MIBG : Markedly increased MIBG activity is identified in the right paraspinal region in a triangular configuration and fiant focal uptake in the left frontal bone

MIR NucMed teaching files, Wash U MO

Teaching pointsThe differential diagnosis for retroperitoneal masses in the adrenal/ renal region for children includes Neuroblastoma and Wilm's tumor.

-Wilm's tumor typically does not calcify, and would have no uptake on bone scan (due to absent calcification) and no uptake on MIBG.

MIBG scintigraphy is more sensitive than bone scan for detection of metastatic disease due to neuroblastoma.

24 hrs I-123 SPECT/CT

15-1-2013

24 hrs I-123 WB

7-8-2012

A 22 years Saudi female patient Status post resection of left side pheochromocytoma and repair of transposition of great vessels, CT showed stable tiny right adernal nodule and two suspicious hepatic lesions. I- 123 MIBG ordered to R/O recurrence.

ADDED VALUE OF SPECT/CT IN NET SCINTIGRAPHY

I-123 MIBG scan

Charles et al’ RadioGraphics 2007

MIP of FDG PET scan

a) Abdominal MR image shows a 7.5 6.9-cm left adrenal mass (arrow).

(b) On an anterior abdominal I-123 MIBG scan (spot view), the mass avidly concentrates radiotracer.

(c) PET was performed as a second whole-body survey for metastases Anterior MIP of FDG PET scan shows strongly positive uptake. FDG accumulates in malignant PHEO (sensitivity of 88%) to a greater extent than in benign PHEO (58%).

A 78-year-old man with recent onset of hypertension and arrhythmias. The patient underwent a work-up for PHEO, which revealed a high level of plasma norepinephrine along with high urine levels of norepinephrine, dopamine, and metanephrine

Other PET Radiopharmaveuticals for NET Imaging

• F-18 FDG (GLUT)

• 18F-dihydroxy-phenyl-alanine (18F-DOPA)

• 11C-5-hydroxy-tryptophan (11C-5-HTP)

F-18 FDG PET/CT

• FDG positron emission tomography (PET) is useful only in patients who are suspected of having aggressive neuroendocrine tumors that are not detected by somatostatin receptor imaging or conventional anatomic imaging.

FDG PET/CT Tc-99m octreotide

(A) 68Ga-DOTATATE and (B) 18F-FDG PET/CT images from a patient with well-differentiated (‘typical’) bronchial carcinoid tumor. The primary tumor (left hilum, arrow) is positive for (A) 68Ga-DOTATATE but negative for (B) 18F-FDG. Histology showed that the left lung had postcollapse pneumonitis that was negative for (A) 68Ga-DOTATATE uptake but positive for (B, broken arrow) 18F-FDG.

From: Irfan Kayani et al; American Cancer Society 2008

A

B

Baum et al; SNM 2008

18F-dihydroxy-phenyl-alanine (18F-DOPA)&

11C-5-hydroxy-tryptophan (11C-5-HTP)

• NET´s belong to the so called amine precursor uptake and decarboxylation (APUD)- omas, ie, they

have the capacity for uptake and decarboxylation of amine precursors like 5-hydroxytryptophan (5-

HTP) or L-dihydroxyphenylalanine (L-DOPA), and subsequent storage or release of serotonin (5-

HT) and dopamine.

• Carcinoid tumors of midgut origin, midgut carcinoids (MGC) produce serotonin via the precursors

tryptophan and 5-hydroxytryptophan. Serotonin is metabolized to 5-hydroxyindole acetic acid (5-

HIAA) and excreted in the urine.

• For midgut carcinoids serotonin, urinary-5-HIAA and chromogranin A (CgA) are the main tumor markers.

• whereas in foregut carcinoids (bronchial carcinoids and endocrine pancreatic tumors (EPT)) and

hindgut carcinoids serotonin production is rare and therefore 5-HIAA is seldom increased.

11C-HTP PET/CT

• Promissing results and high accuracy in pancreatic NET.

• Sens. 96%

• Superior to 18F-DOPA or Octreotide

• HTP PET/CT excellent imaging method in pancreatic islet cell tumors

11C- 5 hydroxytryptophan Somatostatin RS

MEN-1 syndrome and multiple gastrinomas in the pancreas

duodenal gastrinoma Patient with biochemical evidence of a gastrinoma and whereendoscopic ultrasonography indicated a pathological intraabdominal lesion. Both SRS and CT were negative.

11C-5 HTP positive >>>>> duodenal gastrinoma >>>>>conformed in surgery

18F-DOPA• Combined PET/CT –Pheochromocytoma lesion based sensitivity

– DOPA 93% (vs MIBG P<0.05, CT < 0.001)

– 123I-MIBG 76%

• In Meddullary Thyroid Carcinoma (MTC)

– CT/MRI 64%

– DMSA SPECT 19%

– FDG PET 30%

– DOPA PET 71%

– DOPA PET/CT 89%

• FDG may detect more dedifferentiated lesions

• DOPA detects more differentiated lesions

• American Thyroid Association: Calcitonin > 150 pg/mL do 18F-DOPA

• In Congenital hyperinsulinism of infancy (CHI):

[18F]-DOPA PET should be considered as a primary differential diagnostic tool in infantile hyperinsulinemic hypoglycemia

(18F-FDOPA)

BILATERAL PHEOCHROMOCYTOMAS

• Negative in MIBG

INSOLINMA

PET Successful Surgery

18F-DOPA In MTC

18F-DOPA In Congenital hyperinsulinism of infancy (CHI)

Pancreatic tail focal CHI Pancreatic body focal CHI

18F-DOPA In monitoring treatment of (CHI)

• (a) 18F-DOPA PET of a 56-year-old female diagnosed with NETof the pancreas with liver metastases. Note the physiological uptake in the gallbladder (Balan 2005). (b) 11C-5-HTP PET indicating more tumour mass and higher number of liver metastasis.

Ga68-peptide-PET or 18F-DOPA: depends on NET subtype

• Ambrosini 2008: 68Ga 13/13, DOPA 9/13 - 11 foregut tumors

• Haug 2009: 68Ga Sens 96, vs DOPA 56% [n=25] - 11 foregut, 5 unknown, 9 gut tumors

• Montraverse EANM 2010: in ileal carcinoid DOPA superior to Ga68-PET

Pancreas NET Midgut carcinoid

DOPA DOPAGa68-DOTATATE Ga68-DOTATATE

Take Home Message• At this time, no single imaging modality is considered the procedure of choice for neuroendocrine

tumor evaluation.

• Functional imaging is more sensitive and more specific than anatomical imaging.

• Selection of the radiotracer for NET depend on the histological subtypes and location.

• SPECT/CT improve image interpretation in gamma emitter STR radionuclide.

• Although at present it is established that PET tracers as somatostatin analogues labeled with 68Ga are superior to that of gamma emitting agents as regards sensitivity and accuracy, the latter could still represent an accessible alternative specially when PET technology or PET radiopharmaceuticals are not accessible.

• FDG PET/CT has a role in evaluation of aggressive poorly differentiated NET

• [18F]-DOPA PET is a promising diagnostic tool in evaluation of NET especially in MTC and CHI.

• Ga-68 has a future to be the technetium tracer for the PET.

THANK YOU