This document discusses advances in oncological PET imaging. It begins by outlining limitations of current PET/CT imaging related to false positives, false negatives, and radiation exposure. It then describes several advances in PET imaging including new radiotracers for tumor characterization, instrumentation improvements, software enhancements to reduce radiation dose, and hybrid PET/MRI imaging. The document provides examples of how various new radiotracers beyond FDG can provide clinical benefits for tumor imaging and characterization.

1. Dr. Hussein Farghaly, MDDr. Hussein Farghaly, MD
Assistant professor and ConsultantAssistant professor and Consultant
nuclear Medicinenuclear Medicine
Advances in oncological PETAdvances in oncological PET
ImagingImaging

2. Outline
 Introduction
 Limitations of PET/CT imaging
 Advances of PET/CT Imaging:
New PET radiotracer
PET/CT protocols
Soft Wear Enhance the specificity
Insturmentation
PET/MRI
PEM

3. IntroductionIntroduction
 FDG PET/CT has emerged as a powerful imaging tool for the detection of various cancers.FDG PET/CT has emerged as a powerful imaging tool for the detection of various cancers.
The combined acquisition of PET and CT has synergistic advantages over PET or CT aloneThe combined acquisition of PET and CT has synergistic advantages over PET or CT alone
and minimizes their individual limitations.and minimizes their individual limitations.
 It is a valuable tool for staging and restaging of some tumors and has an important role in theIt is a valuable tool for staging and restaging of some tumors and has an important role in the
detection of recurrence in asymptomatic patients with rising tumor marker levels and patientsdetection of recurrence in asymptomatic patients with rising tumor marker levels and patients
with negative or equivocal findings on conventional imaging techniques. It also allows forwith negative or equivocal findings on conventional imaging techniques. It also allows for
monitoring response to therapy and permitting timely modification of therapeutic regimens. Inmonitoring response to therapy and permitting timely modification of therapeutic regimens. In
about one third of the patients, the course of management is changedabout one third of the patients, the course of management is changed

4. Clinical Impact of PET/CT
Advantages of PET/CT over Conventional anatomical imaging:
• Characterizing lesions difficult to biopsy
• Detecting occult cancer
• Determining extent of cancer and response to therapy
Significant clinical impact
 More accurate diagnosis
 Avoidance of unnecessary tests, and (potentially) harmful procedures
 Better treatment or management (PET - CT changes management in about one third of cancer
patient)
Is FDG PET/CT a completely perfect test?

5. Limitations in FDG – PET/CTLimitations in FDG – PET/CT
imagingimaging
Due to FDG:Due to FDG:
False positiveFalse positive
False negativeFalse negative
Radiation exposure from radiotracer (8Radiation exposure from radiotracer (8
mSv)mSv)
Due to instrumentation:Due to instrumentation:
mis-registration (motion artifact)mis-registration (motion artifact)
low spatial resolutionlow spatial resolution
Radiation exposure from CT (7 -25 mSv)Radiation exposure from CT (7 -25 mSv)
Long study timeLong study time

6. Limitations in FDG – PET/CTLimitations in FDG – PET/CT
imagingimaging
 False positive:False positive:
 ““Normal” uptakeNormal” uptake (head & neck, muscle, brown fat, GI/GU uptake)(head & neck, muscle, brown fat, GI/GU uptake)
 false-positive FDG uptake can occur in PET/CT in relation tofalse-positive FDG uptake can occur in PET/CT in relation to
granulomatous disease or inflammation. Some benign tumors, such asgranulomatous disease or inflammation. Some benign tumors, such as
colonic adenomas and fibroids, may also demonstrate intense FDG uptakecolonic adenomas and fibroids, may also demonstrate intense FDG uptake
 False negative:False negative:
 Small lesions (partial volume loss)Small lesions (partial volume loss)
 Hypometabolic lesions (low grade tumor, well differentiated NET,Hypometabolic lesions (low grade tumor, well differentiated NET,
mucinous secreting tumor, RCC, some low grade lymphoma likemucinous secreting tumor, RCC, some low grade lymphoma like
small lymphocytic lymphoma, peripheral T-cell lymphomasmall lymphocytic lymphoma, peripheral T-cell lymphoma
 Elevated serum glucoseElevated serum glucose

7. RADIOCHEMISTRY
INSTRUMENTATION
HW/SW
ADVANCES IN PET IMAGING
NEW SCINTILLATION CRYSTALS
Dose reduction soft wear
PET/MRI
PEM
NEW TRACERS PET

8. Advances in PETAdvances in PET
RadiotracerRadiotracer

9.  Glucose metabolism [Glucose metabolism [1818
F]FDGF]FDG
 Protein synthesis C-11-methionine
 Membrane function [Membrane function [1111
C]CholineC]Choline
 ProliferationProliferation [[1818
F]FLTF]FLT
 HypoxiaHypoxia [[1818
F]FMISOF]FMISO
[18F]FAZA[18F]FAZA
[64Cu]ATSM[64Cu]ATSM
 ApoptosisApoptosis [[1818
F]Annexin VF]Annexin V
 AngiogenesisAngiogenesis [[1818
F]NGR-peptideF]NGR-peptide
 Neuroendocrine tumorsNeuroendocrine tumors [[110110
In]OctreotateIn]Octreotate
[68Ga] DOTATOC[68Ga] DOTATOC
TRACERS for TUMOR CHARACTERIZATIONTRACERS for TUMOR CHARACTERIZATION
Advances in PET RadiotracerAdvances in PET Radiotracer

10. Normal distribution
of FDG and C-11
Methionine
C-11-methionineC-11-methionine
Benjamin et al; 2010 Anticancer Ther. 10(5), 609–613 (2010)
Posterior fossa glioma.

11. C-11-methionineC-11-methionine
(A) 18F-FDG; (B) contrast-enhanced MRI; (C) 11C-MET PET. Glioblastoma in the right
frontal lobe, which is hard to delineate in the 18F-FDG PET. However, amino-acid PET
with 11C-MET clearly shows the lesion with excellent tumor to background contrast.
Benjamin et al; 2010 Anticancer Ther. 10(5), 609–613 (2010)
A B
C

12. left frontal grade II fibrillary astrocytoma (post-left frontal grade II fibrillary astrocytoma (post-
surgery and post-radiotherapy)surgery and post-radiotherapy)
C-11-methionineC-11-methionine
Benjamin et al; 2010 Anticancer Ther. 10(5), 609–613 (2010)

13. 11C-choline11C-choline
Richter et al;, Mol Imaging Biol (2009)

14. 11C-choline11C-choline
Fifty-five-year-old patient with increasing PSA level (1.43 μg/l), 27 months after radical
prostatectomy (Gleason score8). Coronal (left), axial (middle), and sagittal (right) fused image
projections of PET/CT scans. Focal 11C-choline uptake (a) in right (bold arrow) and left (thin
arrow) iliac region revealed lymph node involvement, not observed with 18F-FDG PET (b).
Richter et al;, Mol Imaging Biol (2009)

15. Pure BronchioloalveolarPure Bronchioloalveolar
CarcinomaCarcinomaCT
[11
C]Choline PET
[18
F]FDG PET
SUV = 1.73
Picchio et al; current radiopharmaceutical, 2011

16. Dehdashti et al., Eur J Nucl Med Mol Imaging (2010 5 32:344–350
11C-Acetate11C-Acetate

17. Chitneni et al,; J Nucl Med 2011; 52:165–168
18F-misonidazole (FMISO) PET scans
in RT Planning
HYPOXIA IMAGING
 [[1818
F]FMISOF]FMISO
18F-misonidazole
[18F]FAZA[18F]FAZA
18F-fluoroazomycinarabinofuranoside
[64Cu]ATSM[64Cu]ATSM
64Cu-diacetylbis
( N4-methylthiosemicarbazone)

19. Adapted from MacManus et al, Radiotherapy and Oncology 2013
PET/CT in Radiation Therapy planning

21. GEMINI TFGEMINI TF PET/CT scanner withPET/CT scanner with
TruFlight technologyTruFlight technology

22. Outline
 PET/CT principle
 Indeterminate lung nodules
 Lung cancer
Staging and Restaging of known tumor
Monitoring therapy
Early detection of tumour recurrence
Impact on radiation therapy planning

23. Indeterminate lung nodules
 Accounts for ≈ 20% of newly diagnosed lung cancer
 CXR and CT: not accurate to differentiate benign from
malignant non-calcified pulmonary nodules that are
between 1-3 cm in diameter
 Initial presentation in 20% - 30% of lung cancer
 Morphologic stability over 2 years: reliable sign of
benignity:
 Doubling time of malignant nodules: 30-400 days
 Doubling in volume results in 26% increase in
diameter

24. Visual Analysis:Visual Analysis: nodule activity vs mediastinal blood pool activinodule activity vs mediastinal blood pool activi
Quantitative analysis: SUV (standardized uptake value)Quantitative analysis: SUV (standardized uptake value)
[[1818
F]FDG PETF]FDG PET
Measure of metabolic activity of SPNMeasure of metabolic activity of SPN
SUV = 7.3
CT [18
F]FDG PET
A SPN with SUV more than 2.5 is considered to be malignant

25. PIOPILN Study
Prospective investigation of PET in lung nodules
 90 patients from 5 centers with indeterminate nodules (CT)
 Size range: 0.7 to 4 cm
 All nodules had histology: 67% were malignant
 PIOPLIN and other studies: SUV > 2.5 = visual (FDG uptake > mediastinal
blood pool)
Sensitivity: 90-100% Specificity: 69-95%
 False positive: Active granuloma
 False negative: Bronchioalveolar, mucinous carcinoma, carcinoid
Hyperglycemia (decreases uptake by up to 50%)
 Lowe VJ et al. J Clin Oncol 1998;16:1075-1084.
 Nomori H et al. Lung cancer 2004;45:19-27.
 Herder GJ et al. Eur J Nucl Med Mol Imag 2004;31:1231-1236.
 Lowe VJ et al. J Nucl Med 1994;35:1771-1776.
 Nomori H et al. Ann Thorac Surg 2005;79:984-988.

26. Diagnostic Accuracy of FDG PET and CT for the
Characterization of Lung Nodule
 344 patients for which definite diagnosis was obtained
 Prevalence of malignancy: 53%
 Average size: 16 mm
PETPET CTCT
Sensitivity 91.7% 95.6%
Specificity 82.3% 40.6%
Fletcher JW et al. J Nucl Med 2008;49 (2):179-
185

28. Middle-aged woman with a 1.5 cm lung
nodule
SUV is 6.2

29. Question
What should be done next?
 A. Follow-up
 B. Biopsy
 C. Chemotherapy
 D. Antibiotics

30. Question
What should be done next?
 A. Follow-up
 B. Biopsy
 C. Chemotherapy
 D. Antibiotics

31. Middle-aged patient with a 1.4 cm lung nodule
SUV is 1.2

32. Question
What should be done next?
 A. Biopsy
 B. Reassure the patient that the nodule is benign
 C. Follow-up with CT at 3-6 months interval for
2 years
 D. Follow-up with chest X-ray in 6 months

33. Question
What should be done next?
 A. Biopsy
 B. Reassure the patient that the nodule is benign
 C. Follow-up with CT at 3-6 months interval
for 2 years
 D. Follow-up with chest X-ray in 6 months

34. ACCP Evidenced-Based Clinical Practice
Guidelines: Recommendation for FDG PET
 PET recommended: Probability of cancer low to
moderate (5%-60%) and an indeterminate
nodule measures at least 8-10 mm.
 PET NOT recommended: SPN that has a high
probability of malignancy (>60%) or nodule <
8-10 mm

35. Staging NSCLC
T staging: tumor size
 T1 < 3 cm
 T2 > 3 cm
 T3 > 3 cm with chest wall, pleural, or pericardial extension
 T4 with invasion of adjacent organs
N staging: nodal metastases
 N0: no nodes
 N1: ipsilateral hilar nodes
 N2: ipsilateral mediastinal or subcarinal nodes
 N3: contralateral nodes or scalene/supraclavicular nodes
M Staging: distant metastases
 M0: no distant metastases
 M1: distant metastases present

36. FDG PET for Staging
T staging:
The extent of the primary tumor determines therapeutic management.
Imaging is done to assess the size of the tumor and the extent of pleural,
chest wall or mediastinal invasion.
CT and MRI are useful for confirming gross chest wall and mediastinal
invasion. But they are inaccurate in differentiation between anatomic
contiguity and subtle invasion.
FDG PET alone: limited for T staging due to poor anatomic resolution,
lack of anatomical landmark.
PET/CT: improve staging by clearly demarcating the actual extent of the
tumor and involvement of chest wall, diaphragm, mediastinal pleura or
pericardium or main bronchus (T3 staging).
Padma; et al, 2011.

37. T staging cont.:
 similarly, it is useful to determine the involvement of mediastinal,
vertebral and vital structures, such as the great vessels, trachea,
esophagus or heart (T4 staging).
 Also it is used to evaluate additional pulmonary nodules in the same
lobe/ipsilateral lung having primary lung cancer, and determine the
likelihood of malignancy in these nodules.
 CT is rarely able to differentiate between reactive and malignant
pleural effusion whereas malignant pleural effusion showed FDG
uptake in PET (stage M1a).
 It also has a role in guiding biopsy in patient with disease recurrence.

38. 66 year-old with right hilar mass
Primary lung ca
with atelectasis

39. Lung cancer staging scan with
incidental second primary
Coleman et al; 2006

40. N staging:
•The precise characterization of
mediastinal lymph nodes is crucial
for determining nodal (N) stage
and thus resectability in patients
with NSCLC.
•CT and MRI: limited by size
criteria.
• FDG PET: best to detect tumor
in normal size lymph nodes

41. CTCT
 Depending on size criteria on CT a lymph node with a short-axis
diameter greater than 1 cm is considered enlarged and a
predictor for metastasis. However, this method has proven
inaccurate. In one study, 44% of metastatic lymph nodes in
patients with NSCLC measured less than 1 cm, and 77% of
patients without metastatic lymph nodes had a lymph node
measuring greater than 1 cm in the short-axis diameter.
 Several meta-analyses have reported low sensitivities and
specificities of CT in the assessment of mediastinal lymph-node
involvement, ranging from 50% to 65% and from 65% to 85%,
respectively.
Prenzel et al; 2003.

42. FDG PET/CTFDG PET/CT
 Depending on the metabolic activity within the lymph node
FDG PET can characterize mediastinal LN.
 PET positive mediastinal findings should be histologically
or cytologically confirmed due the fact that FDG is also
taken by inflammatory process.
 In patients with negative mediastinal PET images invasive
staging can be omitted and it is estimated that the introduction
of PET has reduced the number of mediastinoscopies by 65%
 Also in case of central tumors, PET hilar N1 disease, low FDG
uptake of the primary tumour, invasive staging with
mediastinoscopy remains indicated.

43. Performance of different locoregional
staging techniques
(adapted from Toloza 2003).

44. Staging PET/CT in 74-year-old woman with 2.6-cm left lower lobe SCCStaging PET/CT in 74-year-old woman with 2.6-cm left lower lobe SCC
Diagnostic axial contrast-enhanced CT scan
shows multiple small subcentimeter lymph
nodes scattered throughout mediastinum,
primarily in lower left paratracheal region.
Fused axial PET/CT image shows uptake in
lower left paratracheal lymph nodes and 3-
mm lower right paratracheal lymph node
With metastatic involvement, confirmed at mediastinoscopy. Given presence of
contralateral lymph node metastases, patient received chemotherapy and radiation
instead of surgical

45. Initial staging PET/CT for 56-year-old man with 1.8-cm
adenocarcinoma in right upper lobe and long history of sarcoidosis
Axial contrast-enhanced CT scan
shows 1.8-cm right upper lobe
nodule with extensive
mediastinal and hilar
lymphadenopathy
Fused axial PET/CT image confirms intense
uptake in right upper lobe nodule and lymph
nodes. Lymph node biopsies performed during
mediastinoscopy showed only granulomatous
inflammation from sarcoidosis and no evidence
of tumor
Given this finding, patient was sent for curative resection

46. M Staging:
 Common metastases to adrenals, skeleton, liver, brain.
 FDG PET is superior to conventional imaging:
Detect metastases > ~7 mm when CT and MRI are normal or
equivocal
Detect unsuspected distant metastases: ~13% of patients
Stage I: 7.5%
Stage II: 18%
Stage III: 24%
 Change management: 18% of cases
Peterman RM et al N Engl J Med 2000;343:254-261
Baum RP et al. Q J Nucl Med 2004;48:119-142.

47. PET/CT for the Characterization of Adrenal
Masses in Patients with lung Cancer
Giles et al; AJR:192, April 2009

49. Bury T et al. Eur J Nucl Med 1998;25:1244-1247.

55. TubercolosisTubercolosis
SarcoidosisSarcoidosis
AspergillosisAspergillosis
HistoplasmosisHistoplasmosis
CryptococcosisCryptococcosis
False-positive results:False-positive results:
Inflammatory lesions (mainly granulomas)
Limitations of FDG-PET for LungLimitations of FDG-PET for Lung
Nodule Characterization and NSCLC:Nodule Characterization and NSCLC:

56. maxSUV: 2.6
48 year-old female with a pulmonary mass
48 year-old female with a pulmonary mass

58. Histological TypeHistological Type
CarcinoidCarcinoid
Pure Bronchioloalveolar Car (BAC),Pure Bronchioloalveolar Car (BAC),
mucinous camucinous ca
neuroendocrine tumorneuroendocrine tumor
Well differentiated typeWell differentiated type
Lesion Dimension:Lesion Dimension: Small lesion < 6-8 mmSmall lesion < 6-8 mm
% of viable neoplastic% of viable neoplastic
cells in SPNcells in SPN
Limitations of FDG-PET for Lung NoduleLimitations of FDG-PET for Lung Nodule
Characterization and NSCLC:Characterization and NSCLC:
False-negative resultsFalse-negative results
HyperglycemiaHyperglycemia:: > 200 mg/dl = PET not performed> 200 mg/dl = PET not performed

59. [18
F]FDG PETCT
Fused
Lung nodule
4 mm in diameter
?

60. [18F]FDG PETCT
CT- PET
SPN: 4 mm in diameter

61. 52 years woman with an infiltrative lung nodule
maxSUV: 1.9

62. Question
What is the differential diagnosis?
 A. Neuroendocrine tumor
 B. Bronchioalveolar carcinoma
 C. Infection
 D. All of the above

63. Question
What is in the differential diagnosis?
 A. Neuroendocrine tumor
 Bronchioalveolar carcinoma
 C. Infection
 D. All of the above

64. New Techniques to overcome LimitationsNew Techniques to overcome Limitations
of FDG-PET in NSCLCof FDG-PET in NSCLC
 Imprecise physiologic and anatomic registration, most common
adjacent to the diaphragm and heart, can lead to misregistration
artifact. (RESPIRATORY GATING)
 Many processes with increased metabolic activity, such as
infection and inflammation, show increased uptake on PET.
(DUAL TIME POINT TECHNIQUE)
 Tumor with low FDG uptake (Carcinoid,Carcinoid, BAC, mucinous ca,
neuroendocrine tumor, Well differentiated type) OTHER PET
RADIOTRACER.

65. Pure BronchioloalveolarPure Bronchioloalveolar
CarcinomaCarcinomaCT
[11
C]Choline PET
[18
F]FDG PET
SUV = 1.73

66. Dual-Time-Point F-18 FDG PET/CT
E SUV 5.7
D SUV 7.1
PET/CT imaging was performed
60 and 120 minutes after injection

67.  Seth Kligerman1 and Subba Digumarthy: Staging of Non–Small Cell Lung Cancer Using
Integrated PET/CT. AJR 2009; 193:1203–1211.
 Dominique Delbeke: Role of FDG PET and PET/CT Imaging in Indeterminate
Pulmonary Nodules and Lung CancerCongreso Chileno de Medicina Nuclear, Santiago,
Chile 13-14 Noviembre 2008.
 Padma S, Shanmuuga P. and Shamily G.: Role of PET in carcinoma lung evaluation:.
Journal of cancer rearach and therapeutics-April-June 2011-Volume 7-Issue 2.
 Didier Lardinois: Pre- and intra-operative mediastinal staging in non-small-cell lung
cancer. Swiss Med Wkly. 2011;141:w13168.
 Kiyoshi Shibuya, Kenzo Hiroshima and Takehiko Fujisawa: Comparison of
Endobronchial Ultrasound, Positron Emission Tomography, and CT for Lymph Node
Staging of Lung Cancer. Chest 2006;130;710-718
 Khaled Alkhawaldeh,, Hans-J Biersack,, Anna Henke,, and Samer Ezziddin: Impact of Dual-Time-
Point F-18 FDG PET/CT in the Assessment of Pleural Effusion in Patients With Non–
Small-Cell Lung Cancer. Clin Nucl Med 2011;36: 423–428)
ReferencesReferences

68. Why PET-CT?Why PET-CT?
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