Overview of radionuclide functional imaging of NET

2. Radionuclide Functioning Imaging of
Neuroendocrine Tumors (NET)
Hussein Farghaly, MD
Assistant Prof. and Consultant of Nuclear Medicine
Assiut University-Egypt
2014

3. 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

4. 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).

6. 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)

7. Indication Of NETs Radionuclide
Imaging

8. 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)

9. Somatostatin and Octreotide:
Molecular Characteristics
Amino acids essential
for receptor binding
ala gly cys lys asn phe phe
cys ser thr phe thr
lys
trp
phe cys phe
thr
ol
cys thr
lys
D
trp
OctreotideHuman somatostatin
Harris AG. Drug Invest. 1992;4(suppl 3):1-54.

10. 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

11. Radionuclide for Somatostatin receptor Imaging
SSR Radiotracer Source Injected
dose
Imaging 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
+Auger
electrons
Tc-99m- Octreotate
Tc-99m- Octreotide
Tc-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
period
T1/2: 68 minutes
PET/CT 3-4 mSv

12. Results of the clinical application of somatostatin receptor imaging
using various ligands in patients with
gastroenteropancreatic neuroendocrine tumors

13. Normal distribution in radio labeled SR analog

14. Causes of potential misinterpretation of results with octreotide scintigraphy

16. 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

17. • 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 images
Is this a normal octreotide scan?
Teaching point
Knowing normal biodistribution of In-111 octreotide is very
important as it was the key in this case.

18. 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

19. • 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)

20. 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

21. 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.

22. 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,

23. 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 initially
showed no remarkable change in
liver lesions
68Ga-DOTATOC PET scan in treatment monitoring
Gabrie et al; J Nucl Med 2009; 50:1427–1434

24. Baum et al; SNM 2008

25. Middle age woman with longstanding
history 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
radionuclide
therapy 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 scan68 Ga-DOTATATE

26. Baum et al; SNM 2008

27. • 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

28. 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 abdomen
and 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 points
Paraganglioma 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

29. 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 points
The 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.

30. 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

31. 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

32. Other PET Radiopharmaveuticals
for NET Imaging
• F-18 FDG (GLUT)
• 18F-dihydroxy-phenyl-alanine (18F-DOPA)
• 11C-5-hydroxy-tryptophan (11C-5-HTP)

33. 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.

34. FDG PET/CTTc-99m octreotide

35. (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

36. Baum et al; SNM 2008

37. 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.

38. 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

39. 11C- 5 hydroxytryptophan Somatostatin RS
MEN-1 syndrome and multiple gastrinomas in the pancreas
duodenal gastrinoma
Patient with biochemical evidence of a gastrinoma and where
endoscopic ultrasonography indicated a pathological
intraabdominal lesion. Both SRS and CT were negative.
11C-5 HTP positive >>>>> duodenal gastrinoma
>>>>>conformed in surgery

40. 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

41. (18F-FDOPA)
 BILATERAL PHEOCHROMOCYTOMAS
• Negative in MIBG
 INSOLINMA
 PET Successful Surgery

42. 18F-DOPA In MTC

43. 18F-DOPA In Congenital hyperinsulinism of infancy (CHI)
Pancreatic tail focal CHI Pancreatic body focal CHI

44. 18F-DOPA In monitoring treatment of (CHI)

45. • (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.

46. 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

47. 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.

48. THANK YOU