Positron Emission Tomography: A Practical Review of Clinical Applications

and a Self-examination

Neville Irani1 MD, Jorge Vidal

2 MD, Natasha Acosta

2 MD,

Mark Redick2 MD, Akash Sharma1 MD.

St. Luke’s Hospital of Kansas City

105105thth Annual Meeting of the Annual Meeting of the American Roentgen Ray SocietyAmerican Roentgen Ray Society

1Allegheny General Hospital, Pittsburgh, PA2St. Luke’s Hospital of Kansas City/ UMKC, Kansas City, MO

Radioactive Decay & Nuclear Imaging

• Isomeric transition

• Alpha• Beta -• Beta + [positron]• Electron Capture

ExampleExample

• 99mTc 99Tc+

• 18F 18O+++

RememberRemember: In AX, A = atomic mass (# protons + neutrons)

Tc = Technetium [nuclear medicine workhorse] F = Fluorine [Most widely used PET Agent]U = Uranium O = OxygenTh = Thorium Kr = KryptonPa = Protactinium Br = Bromine

Positron Basics• A Positron is a positively charged

electron emitted during the decay of a proton to a neutron in the atom’s nucleus.

• During decay, the positron that exits the nucleus encounters an electron, usually within 2-16 millimeters. The subsequent annihilation results in two annihilation photons which travel in 180° opposite directions.

NP

e-+

Positron Radionuclides

Most positron emitters have high energy photons but short half-lives:

Positron Source Half-Life (minutes) Maximum Energy

11C = > 11B

20

960keV

13N => 13C

9

1.19 MeV

15O = > 15N

2

1.72 MeV

18F = > 18O

110

640 keV

68Ga = > 68Zn

68

1.89 MeV

82Rb = > 82Kr

1.3

3.35 MeV

Note: Mean photon energy for 18F is 511 keV.

• Most positron emitters are created at a cyclotron facility. Up to 1-2 Curies of 18F are produced per cycle by bombarding 18O with protons. Typical clinical patient dose is 10-20 mCi.

• An ideal PET agent should be available to the patient within 1 half life. 18Fluorine has a half-life of about 2 hours allowing adequate time for transportation.

• For this reason, 18Fluorine tagged biologic compounds are the most practical positron radiopharmaceuticals.

Why 18Fluorine?

• The most commonly used positron radiopharmaceutical to date is 18F conjugated with glucose to form

Fluoro-DeoxyGlucose [FDG].

Radiopharmaceuticals

Radiopharmaceuticals are made by conjugating a radioactive atom with a biologically active compound.

Bone scans, for example, are done with 99mTc conjugated with MDP (99mTc - MDP).

How FDG Works• Following injection, during the distribution phase (usually one

hour) cells take up and phosphorylate FDG. Non-phosphorylated FDG is excreted by the kidneys.

• Phosphorylated FDG does not proceed to the next step in glycolysis due to altered configuration (substitution of Fluorine for a hydroxyl group).

• Malignant cells demonstrate a difference in accumulation due to increased cell membrane transporters and underexpression of glucose 6-phosphatase.

• This leads to a greater tumor to background uptake, thereby differentiating malignant lesions from benign tissue.

How FDG Works

CELL

MEMBRANE

Glu

t Tra

nsp

ort

er

Hexokinase

Phosphotase

18Glucose

Hexokinase

Phosphotase

18Glucose

18Glucose-6-P

Glu

t Tra

nsp

ort

er

Normal cells

Abnormal Cells

18Glucos

e

18Glucose-

6-P

18Glucose

Common Indications Medicare Approved:

• Solitary Pulmonary Nodule

• Lymphoma

• Colorectal Cancer

• Lung cancer

• Head and Neck cancers

Not Yet Approved:

• Ovarian, GYN tumors

*Better than CT for Peritoneal carcinomatosis

• Testicular cancer

• Pancreatic cancer

• Melanoma

• Thyroid Cancer

• Breast Cancer

• Alzheimer’s Dementia

• Myocardial Viability

Common Oncologic Applications

• Initial staging of biopsy proven cancer (prior to any treatment)

• Restaging after irradiation, chemotherapy, or surgical resection.

*Serves as an indicator of response to therapy -- some treatment protocols

base regimen changes upon SUV differences.

• Rarely, diagnosis of malignancy. e.g. indeterminate solitary pulmonary nodule on CT scan

FDG-PET has Low Sensitivity for:• Prostate Cancer [C-11 Acetate PET shows promise]

• Renal Cell Carcinoma

• Hepatocellular Carcinoma

• Mucinous carcinomas

• Neuroendocrine tumors [use MIBG instead]

• Bronchioalveolar carcinoma

• Teratoma or ovarian adenocarcinoma

• CNS neoplasms [due to high background uptake]*

• Villous adenomas

• Adrenal Adenomas

* PET is helpful in distinguishing scarring and necrosis from recurrent tumor following treatment.

Physiologic Uptake Seen in– Brain

– Heart [non-fasting; during fasting fatty acids are preferentially used]

– Kidney [Unlike glucose, FDG is not reabsorbed in the proximal tubules]

– Liver

– Intestinal Mucosa [especially when loops are clustered together]

– Skeletal and smooth muscle (neck, larynx, diaphragm)

– Laryngeal muscle and muscles of mastication [esp. if pt is talking]

– Periareolar breast [esp. lactating breast]

– Thymus [in children]

– Bone Marrow [normally increased post-chemotherapy or following Colony Stimulating Factor administration]

– Thyroid [in grave’s disease]

All have low intracellular glucose-6-phosphate high glucose uptake and utilization.

Normal FDG UptakeLarynx

Intestinal Mucosa

Left Ventricle

Patchy Atrial uptake

Salivary Glands

Liver

Base of Tongue

Base of Brain Ureter

KidneysBladder

Marrow Uptake

Quantification of PET Data

• On CT, each pixel in the field of view represents a Hounsefield unit (HU) of attenuation to x-ray transmission (water = 0 HU; bone 1000 HU).

• On a PET image, each pixel represents the number of coincident photons (> 480 keV) originating from FDG uptake at that position.

• SUV is a ratio to compare relative uptake in a Volume of Interest compared to expected background uptake.

)(_)(_

)/(_

kgWeightPatientmCiDoseTotal

kgmCiionConcentratTissueSUV

Standardized Uptake Value (SUV)

• Initial studies using SUV were done in studying pulmonary nodules led to an SUV of 2.5 as demarcation of benign from malignant pulmonary lesions.

• Higher SUV in pulmonary lesion is an independent predictor of poorer prognosis.

– Ahuja V, Coleman RE, Herndon J, Patz EF Jr. Cancer. 1998 Sep 1;83(5):918-24.

• It’s a good practice to report the maximum SUV in the ROI.

• Mean SUV is dependent upon the ROI and sensitivity is more important in oncologic imaging.

Inter-examination SUV variation

(within the same patient) may be due to:

• Serum glucose level– Hyperglycemic state will result in false negative scan

• Fasting vs. Non-fasting [affects cardiac uptake]

• Change in body fat [fat cells don’t take up FDG]

• Duration between injection and imaging

Non-malignant causes of FDG uptake

• Inflammatory changes– Inflammatory bowel disease [CRP is usually also elevated]

– Reflux esophagitis & Gastritis

– Active granulomatous disease

– Pneumonitis

– Radiation-induced inflammation

– Conjunctivitis

– Degenerative joint disease

• Post-Exercise increased muscle uptake

• Hyperinsulinemia (increased muscle uptake)

Fasting = Less Cardiac Uptake

Gastritis, Inflammatory Hilar Nodes

Normal Patchy atrial Uptake;This patient was likely not fasting

*Usually it is difficult to differentiate physiologic vs inflammatory uptake on PET alone

Image Acquisition

• The diagnostic images shown so far are processed by applying attenuation correction.

• Fewer photons from deeper body structures are detected due to attenuation from surrounding tissue prior to registration on the crystal surface.

• Transmission images are, therefore, acquired with an emission source such as 137CS (662keV), 68Ge or a CT scanner’s x-ray source.

• The amount of attenuation in the transmission images at a given position is then used to correct the emission image and produce the attenuation corrected image.

Image Construction

Emission*Non-attenutation corrected

[NAC]

Transmission

Attenuation

corrected

[AC]

Clinical Value of emission images

• Occasionally lesions in liver can be masked by heterogeneity from attenuation correction. Small lung lesions may be missed due to smoothing effect of correction.

• Improper correction can result from metallic implants and retained bowel contrast causing pseudo-hot spots to appear on attenuation correction images. This occurs mostly when using CT transmission attenuation data for attenuation-correction.

Attenuation Correction

Attenuation Corrected

[AC]

Emission Image

Liver metastasis is more apparent on emission image

Acquisition - Transmission Imaging

Field Of View

Transmission Image Example

Imaging in one plane with triangular phantom gives relative attenuation

Detector array

Photon source

0 2 236863 0

Transmission Image Example

Imaging in perpendicular plane with same phantom

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rce

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e cto

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Composite Summation Image

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Complete ring or circular detector will do this in more than just two directions resulting in better resolution and sharper image

Emission Coincidence Detection

• The positron emitted from the Fluorine nucleus only travels a short distance before annihilating with an electron and producing two equal energy (511 keV) photons which travel in exact 180° opposite directions.

• Conicidence detection distinguishes photons from a true events at a site somewhere along a line between two detectors located directly opposite each other in the ring from scatter photons. Less than 1% of photons included in making the image will be due to scatter if you use this method to ‘screen the photons’.

Photon Coincidence

Coincidence Detection in Field of View

Detector Signals

Coincident photon energies at each detector can be put into a matrix similar to the transmission data to construct an intensity-weighted image

*Minimum photon energy allowable for inclusion by detector is about 480 keV

Represents true event

Represents Scatter

Ideal Detection System

• Dedicated PET scanner – (full ring of gamma detectors).

• Best resolution: 3-7 mm– depends on total number of

detectors

• Scatter photons included in image only 1% of time

Image courtesy of http://tezpur.keck.waisman.wisc.edu/ PET.html

Cheaper Alternative for PET Imaging

• Coincidence SPECT system – Incomplete detection ring

• Cheapest solution but resolution is only 5-10 mm

• Wastes many photons; longer scan time or higher dose required than dedicated PET

Another SPECT Modification

• Modified SPECT– High Energy NaI collimator for

511 keV

• Photons are imaged without coincidence counting

• High photon attenuation; poor resolution (15-30 mm)

• Longer acquisition time than dedicated PET

Patient Exposure: Effective Biological t1/2

• Typical PET examination is done with 10-20 mCi of FDG.

• Increasing starting counts to compensate for poor photon detection with modified SPECT systems will increase patient exposure.

• In general, modified SPECT systems should be avoided.

PhysicalicBio

PhysicalicBioTEffective

log

log_ 2/1

Fusion of 3D Imaging Modalities

Self-Examination

• The following ten cases review most of the concepts we have covered.

• These cases also demonstrate the variety of display methods possible to display PET images: color vs. grayscale, sequential multi-planar images vs. multi-planar maximum intensity projection [MIP].

Fusion of 3D Imaging Modalities

Case 1

• Patient with lymphoma

• Pre and post-treatment PET scan,

multi-planar images at same level.

• PET used to determine whether to change current regimen - 5 months elapsed between pre and post-treatment imaging.

Effective treatment regimen

Pre-Rx

Post-Rx

Resolution of mediastinal & retroperitoneal lymphadenopathy

Normal Penile Uptake

Normal bowel Uptake

Fusion of 3D Imaging Modalities

Case 2

• Solitary pulmonary nodule on CT

-- evaluate for malignancy.

Most Likely Benign SPN

No lung uptake; this lesion was a hamartoma. Keep in mind that some malignant lesions can have false negative PET...

CT PET MIP

Fusion of 3D Imaging Modalities

Case 3

• Unresolved ‘pneumonia’ x 6 months

Broncho-Alveolar Cell Carcinoma

CT PET MIP

PET has poor sensitivity for BAC and is often falsely negative! This one just happened to have enough FDG avidity to be detected. Don’t forget the serendipitous findings. This patient has hydronephrosis.

Fusion of 3D Imaging ModalitiesCase 4

• Cough and hemoptysis

Selected MIP images from PET

Brown Fat Physiology

FDG avid Nodule

Brown Fat and LUL Mass

• LUL mass with SUV 2.1, concerning for malignancy. Infectious process is also possible.

• Extensive uptake in the paraspinous and supraclavicular regions noted bilaterally consistent with activation of brown fat. Brown fat is activated to generate heat (such as when the patient is shivering). Glucose is required to fuel this process. Increased muscle activity is usually also seen in cold or tense patients and part of the increased paraspinal uptake may also be due to paraspinal muscle activity.

Fusion of 3D Imaging ModalitiesCase 5

• Patient had CT showing a lung mass.

Assess for malignancy

Fusion of 3D Imaging ModalitiesCT Chest

Continued

Fusion of 3D Imaging ModalitiesPET Done 1 Month Later

Malignancy in larynx (note asymmetry on CT), lung (biopsy proven small-cell carcinoma), and mid-retro-peritoneum (not appreciable on prior CT).

Fusion of 3D Imaging ModalitiesCase 6

• Patient post right hemicolectomy for cancer presents with retroperitoneal stranding on CT- hemorrhage or metastatic tumor?

• Proposed chemotherapy is contraindicated in a patient with active hemorrhage.

• PET and CT Images were fused to better correlate functional and anatomic findings

(Software-based) PET-CT Fusion

High uptake – Recurrent tumor much more likely than Hemorrhage

Fusion of 3D Imaging Modalities

Case 7

• Patient with lung cancer to undergo radiation treatment.

• Planning CT shows RLL atelectasis -- can’t exclude tumor in this region.

• PET recommended to determine whether to include this portion of lung as well within radiation portal.

(Software-based) PET-CT Fusion

Avid uptake at hilar mass superior to atelectasis

Continued

(Software-based) PET-CT Fusion

Non-FDG avid RLL = no significant tumor. Do not irradiate this region

Case 8

• Initial staging for biopsy proven colon cancer.

• Simultaneous acquisition PET, CT, and fusion imaging provided.

Coronal PET MIP Images

Metastatic focus?

AC NAC [emission]Continued

Courtesy of Barry A Siegel, M.D. -- Mallinckrodt Institute of Radiology, St. Louis, MO.

PET Fused PET-CT CT

Barium

Courtesy of Barry A Siegel, M.D. -- Mallinckrodt Institute of Radiology, St. Louis, MO.

CT Attenuation Correction Artifact

• The apparent metastatic focus is an over-correction artifact due to residual barium in the patient’s colon.

• This artifact is a product of an error in most algorithms using CT transmission attenuation data to correct PET emission images.

• The heavier density of barium is not accounted for by the lower density value assignment for bone (usually the highest preset value in Hounsfield range on CT) which results in the over-correction..

Case 9

• 61 yo for colorectal restaging

• CT shows a large low attenuation lesion in the liver. Evaluate for metastatic disease.

• Software fusion of CT/PET provided.

61 yo for CRC Restaging

Continued

Fusion of 3D Imaging Modalities

61 yo for restaging

• Fusion with CT image shows the photopenic area to match the low attenuation lesion.

• PET shows low FDG uptake in this region; unlikely to be a metastatic deposit -- pattern is compatible with large hepatic cyst.

• If the border of this lesion on PET showed high activity the differential would be abscess, hematoma, or large centrally necrotic tumor.

Fusion of 3D Imaging Modalities

Case 10

• Patient with glioblastoma with abnormal signal on MR close to site of previous tumor

• Is this post-surgical scar or tumor?

• Software MR/PET fusion provided

Fusion of 3D Imaging ModalitiesPET of Whole Brain

Notice diminished uptake in right cortex due to resection / necrosis

Uptake next to prior resection

Fusion of 3D Imaging ModalitiesMR fusion with PET

Recurrent tumor

Fusion vs simultaneous acquisition• Simultaneous acquisiton of PET

and CT images avoids

– Interval change in lesion if enough time passes between acquisitions

– Gross Software misregistration

• Transmission data can be acquired with CT portion of scan = reduced scan time

• Decreases artifacts due to differences in patient positioning

Future of PET imaging …

Other (target-specific) radiopharmaceuticals

• Ammonia (13NH3) imaging for cardiac lesions.

• Na18F for bone scans for non-FDG avid metastatic disease.

• 11C acetate for prostate cancer.

Ammonia PET -- Dilated Cardiomyopathy

Normal NaF bone scan using PET…

• Gives higher resolution compared to Technetium bone scans.

Thank You

• We hope you enjoyed this basic tutorial on PET imaging.

• Any comments are welcome at:– nirani @ wpahs.org– vidalja@ umkc.edu

References

• Mettler FA Jr., Guiberteau MJ. Essentials of Nuclear Medicine. 4th ed. W.B. Saunders Company, 1998.

• Ruhlmann J, Oehr P, Biersack HJ (eds.). PET in Oncology Basics and Clinical Applications. Springer-Verlag, 1999.

• Delbeke D, Martin WH, Patton JA, Sandler MP (eds.). Practical FDG Imaging: A Teaching File. Springer-Verlag, 2002.