A Doctor's Guide to PET imaging
Introduction
PET is an established diagnostic modality with broad uses, particularly in cancer diagnosis and management. It has been available in Australia since 1992, at the Royal Adelaide Hospital since 2000, and as PET/CT since 2005. Following validation at a number of leading Australian Hospitals (including the Royal Adelaide Hospital) in the first years of this century, Medicare rebates are now being progressively made available so that selected studies will be available more widely.
NOTES:- In the following case studies, patient names are fictitious.
- Animations may be enlarged for viewing, but images may be up to 1 MB in size.
Q What are the similarities between PET and conventional imaging Nuclear Medicine studies?
A Both use the localisation of molecules (labelled with a radioactive element) into a physiological or pathological process for diagnostic purposes, and both use sophisticated imaging equipment to map the distribution of these tracers.
 "Fig 1: A dual headed gamma camera/CT - click to enlarge (98kb)") |
| Fig 1: A dual headed gamma camera/CT |
Q What are the differences?
A Conventional tracers (most frequently 99mTechnetium) are generally produced in nuclear reactors and a relative excess of neutrons in their nuclei causes their instability. Generator systems allow weekly distribution of bulk supplies (which can even be delivered to Australia from Europe or North America). These tracers may be bound to a large selection of radiopharmaceuticals. As these atoms decay, a gamma ray is released from the nucleus, which is detected by a gamma camera (fig 1), which may acquire images in planar, dynamic or tomographic modes (Single Photon Emission Computed Tomography, SPECT).
 "Figure 2: Click to enlarge and view caption (17kb)") |
| Fig 2: The PET/CT camera at the Royal Adelaide Hospital |
PET tracers are usually produced in particle accelerators (cyclotrons), and unstable because of a relative surplus of protons, hence represent a class of radioactive substances not generally available from nuclear reactors. In their radioactive decay, they emit positively charged electrons (positrons), which are antimatter. These positrons rapidly encounter electrons, and in the antimatter-matter annihilation which follows, the mass changes to energy (gamma rays) of which 2 are produced and are emitted at exactly 180º. These two gamma rays can be detected by devices which are similar in principle to gamma cameras but are optimised to the appropriate physics and energies of these positron-induced gamma rays (fig 2). Modern imaging of positron tracers is virtually always tomographic, hence the "Positron Emission Tomography". Note, however even in PET it is gamma rays and not positrons per se which are detected.
PET cameras have intrinsic advantages in resolution over standard gamma cameras, and hence the images are frequently of very high quality. Modern PET cameras are mounted on the same gantry as an X-ray CT scanner, allowing co-registration of simultaneously acquired images.
Q If PET has all these advantages why is it not more widely used?
A There are a number of disadvantages. The most used PET radionuclides are listed in Table 1. Note that with good, rapid chemistry it is theoretically possible to label virtually any organic molecule with one (or more) of carbon, nitrogen or oxygen. Unfortunately, because of the very short half-lives of these tracers, there is not time to manufacture molecules which need time-consuming syntheses, and the short half-life necessitates a new batch to be produced for virtually every patient. For this to occur, the cyclotron also needs to be on-site. The expense of all of these factors therefore has meant that PET using these molecules has produced very valuable information on fundamental physiology and is a research tool, but has never crossed into the clinical domain.
The final radionuclide in the list, Fluorine, has, however, a half-life which is sufficient to allow synthesis of molecules, which may then be distributed. Indeed, daily deliveries from Melbourne to Adelaide allow studies to be performed despite the absence of a cyclotron.
The most important tracer is 2-18Fluoro 2-Deoxy-D-Glucose, (FDG) (Fig 3), an analogue of glucose (with a single OH group replaced with 18F) which is transported into glycolytic cells, but not metabolized. It therefore accumulates within cells, allowing high quality images to be obtained after about an hour of accumulation. All PET images in this issue use FDG as the tracer. Dr Henry Wagner, a pioneer of Nuclear Medicine designated 18FDG as "molecule of the (20th) century"
TABLE 1
| Radionuclide |
Half-Life |
  Fig 3: Structure of FDG |
| 11Carbon |
20min |
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| 13Nitrogen |
10min |
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| 15Oxygen |
2min |
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| 18Fluorine |
110min |
Q How do I arrange PET scanning?
AAt the present time, Medicare rebates (mostly $900-$1100) are available only for referral by specialists to designated centres. Referrals outside these conditions and indications, if accepted by the PET centre, will likely generate a charge.
Table 3: Indications for PET scanning for which Medicare rebates are available
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Diagnosis |
Staging |
Restaging/Surveillance |
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| Cervical cancer |
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| Epilepsy |
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 "Fig 4a. Click to enlarge (647kb)")
 "Fig 4b. Click to enlarge (202kb)") |
 "Fig 4c. Click to enlarge (877kb)")
 "Fig 4d. Click to enlarge (271kb)") |
 "Fig 4e. Click to enlarge (1.1MB)")
 "Fig 4f. Click to enlarge (282KB)") |
Fig 4(a to e): Normal FDG PET scan. Typical "eyes to thighs" view used in oncology. |
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Q What structures may normally take up FDG?
AGlucose is the main energy source of the brain, and therefore there is intense uptake within the brain, but paradoxically the brain is frequently not included in routine scans performed for oncology (time taken to image it cumulatively for 5 patients may prevent an extra study being performed and MR and CT better in detecting brain metastases). If insulin levels are high (non-fasting) then there may be high levels of uptake in both cardiac and skeletal muscle. Skeletal muscle uptake may be seen if there is muscular activity during the uptake period (eg cervical muscles in the anxious). Low-level uptake is seen in the liver, and gut uptake may be seen to a variable extent (stomach and colon), presumably due to smooth muscle activity.
There is usually intense tracer concentration in the bladder and renal collecting system. This is because FDG is not reabsorbed by the renal tubules after filtration as would be glucose. If pelvic disease is suspected (eg recurrent rectal carcinoma) catheterisation prior to scanning or manoevres to fill the bladder with dilute urine are sometimes indicated.
Acute inflammatory processes and many malignant tissues concentrate FDG.
Mr S Court is a 59 year old ex smoker who presented with cough. Chest x-ray and diagnostic CT showed a mass, malignant on sputum cytology. A PET scan was requested for staging
Q What does the PET scan show?
| Fig 5: Rotating fused PET/CT images of lung lesion |  "Figure 5 - PET/CT of lung cancer - click to enlarge (984kb)") |
A The fused PET/CT image is shown. This shows the primary lesion in the posterior right lung, extensive hilar uptake and metastases in the anterior mediastinum and liver. Clearly the cancer is inoperable..
Q What are the indications for PET scanning in association with a pulmonary opacity?
AThe widely accepted indications include
- Differentiating between benign and malignant solitary pulmonary nodules (few malignant nodules are "cold" on scanning, but intense inflammation eg sarcoid, TB may be "hot" and therefore false positive).
- Staging known pulmonary malignancy, particularly non small-cell cancers (CT, for example, may detect "enlarged" lymph nodes and imply they are involved with tumour. PET detects malignancy as a "hot" spot and is both more sensitive and more specific). Distant metastases also show up on the PET scan. Upstaging of malignancies will prevent futile attempts at cure
- Detecting recurrence in post operative and post radiotherapy scars.
- False negative results may occur in lesions <1.5 cm, and slow-growing malignancies such as bronchoalveolar cancer and carcinoid.
- The data exists for "non small cell lung carcinoma". Small cell cancer is generally inoperable and has a prognosis uninfluenced by therapy.
 "Fig 6: Liver metastases - Click to enlarge (968kb)") |
Fig 6 :fused PET/CT image showing solitary liver metastases and right sided colonic uptake |
Mr Duke has a known history of rectal cancer treated with surgery and pelvic radiotherapy. Two years later his CEA has increased, and a CT scan has shown a probable lesion in the liver. A PET scan was ordered.
Q What does this show?
A The CT scan (fig 6) shows a single lesion in the left lobe of the liver (probably segment 3). No other lesions were seen in the other slices. There is also uptake in the right side of the colon, most pronounced near the hepatic flexure.The PET scan was ordered to confirm that the lesion was single prior to attempted curative surgery. The liver lesion indeed appears solitary, but the hepatic flexure lesion was a recurrence at the anastomosis, and the ascending colonic uptake was due to colitis. It is possible this Radiation induced.
Q What are the indications for PET in colorectal cancer?
A Colorectal cancer is usually diagnosed by more conventional means and PET scanning has little value in primary staging.
PET scanning is useful in recurrent disease if
- It has been detected by conventional imaging (eg CT, ultrasound) and further lesions need to be excluded such as prior to excision of solitary hepatic metastases for attempted cure.
- Recurrence is suspected but anatomical site not known (eg rising CEA)
- Possible recurrence in a known lesion (eg pelvic scar) seen by conventional imaging is suspected. PET further characterises the pathology.
Q Are there any malignancies in which PET has limited indications?
A PET has limited impact in conditions with
- Relatively low uptake,
- Where the lesion is adjacent to normal high activity structures,
- Where the lesions are small (<1.5cm),
- Where the differential diagnosis includes inflammatory conditions or benign conditions with marked uptake.
Examples of these are:
- Carcinoid
- Prostate cancer
- Pancreatic cancer
- Soft tissue sarcomata
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| Fig 7: Projection PET images of thigh hibernoma (a benign fatty tumour). Malignancy could not be ruled out on these images because of the high uptake, and the images could be consistent with liposarcoma. Note the physiological uptake in the testes. |
Figure 7 shows uptake in a subcutaneous mass thought clinically to be a benign lipoma, but shown on biopsy to be the benign fatty tumour, hibernoma, which shows FDG uptake because of its metabolic rate, rather than malignancy.
Mrs Jackson age 40 has intractable epilepsy. MRI (fig) has shown a lesion, and biopsy has shown a low-grade glioma. Post biopsy the lesion has rapidly progressed. An FDG PET scan was performed. (fig 9 ,10)
Q. What does this show?
 "Fig 8. Possible high grade glioma - Click to enlarge (169kb)") |
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Fig 8 (animation) and 9: Projection FDG brain scan showing intense uptake in left posterior frontal region most likely representing a high-grade glioma. Metastatic disease and abscess are much less likely. Fig 10: Same case as left showing transverse, sagittal and coronal FDG PET images of the brain with intense uptake in the pathological lesion. Pre (A) and post biopsy (B) MRI scans through the lesion. |
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A There is an intense focus of increased FDG uptake in the left posterior frontal region, most likely showing a high-grade glioma. Fig 9 shows projection images, fig 10 slices and MRI.
Q What indications does FDG PET have in neurology?
A The more established indications include
- The assessment of tumours, with uptake greater than brain seen in grade III and IV gliomas. Usually these can be diagnosed with conventional imaging with biopsy, but there are occasions in which the assessment of the grade of tumour, or the localisation of viable tumour in post-surgical or post radiotherapy scarring may be of use.
- Epilepsy: Although FDG uptake would be expected to be increased in an epileptogenic focus if injected at the time of seizure, this is logistically difficult, and reduced activity is usually seen at the focus inter-ictally. This can be complementary to information obtained from MRI or ictal SPECT.
- Dementia and other neurodegenerative disease: This indication is not reimbursable. There is no doubt that advanced Alzheimer’s disease shows a typical reduction in FDG uptake in the posterior parietal regions, frontal dementias reduced activity in the frontal regions (often asymmetric), and diffuse Lewy Body disease more diffusely, but these changes are difficult to demonstrate in the individual in the early clinical course of the disease (fig 11).
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| Fig 11: FDG PET studies (transverse brain scans) of four different patients.
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Group changes in FDG distribution in populations with psychiatric disease, and changes in uptake of specialised tracers (eg 18F-DOPA) in movement disorders such as Parkinson’s disease have been demonstrated, but have not established themselves outside very specialised centres. Research studies are establishing tracers with active uptake in Alzheimer’s disease even pre clinical presentation (and no uptake in normals). These may be available in a few years.
 "Fig 12: PET/CT lymphoma images - click to enlarge (897kb)") |
Fig 12 (left): Projection FDG PET/CT studies performed in a patient with biopsy proved non-Hodgkin’s lymphoma, prior to treatment. After 6 cycles of chemotherapy ). No residual disease could be detected in the later scan. |
Fig 13a & b: Active and Inactive brown fat deposits |
 "Fig 13a. Click to enlarge (795kb)")
 "Fig 13b. Click to enlarge (711kb)") |
Mrs Ann Arbor is 48 years old. Fig 12 shows an FDG PET/CT scans.
Q What is the diagnosis?
A Mrs Arbor has intermediate grade non-Hodgkin’s lymphoma. PET is very sensitive and specific in lymphoma, generally detecting more sites of disease than conventional imaging in initial staging, and as well as showing early reduction in uptake during successful therapy, is also useful in determining if residual masses seen on CT are scar tissue or active disease.
Debate still exists about the timing of follow-up scans and at what stage on incomplete response the decisions to change treatment should be made. The scan shows extensive cervical, axillary and soft-tissue lesions below the diaphragm. Fig 13a shows a mimic of lymphoma, “brown fat” which is used as a source of heat in cold weather. The distribution, usually in young people is typical, and should not be mistaken by an experienced laboratory. Fig 13b shows disappearances of this with a repeat scan with the patient kept warm.
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| Fig 14: FDG PET (resting), left, with 99mTc tetrofosmin study in same patient displayed in short axis (A), vertical long axis (B) and horizontal long axis (C). note FDG uptake with corresponding reduction in perfusion in the interventricular septum (arrows) indicating compromised, but viable myocardium. There is no perfusion or viable myocardium at the apex suggesting old infarction. |
Q Does FDG PET have a role in cardiac disease?
A Figure 14 shows FDG PET of the heart on the left, with stress tetrofosmin (SPECT) study on the right. Viable, but ischaemic myocardium uses glycolytic metabolism (produces lactate) and FDG will accumulate in this myocardium. This same region will demonstrate a defect on the conventional perfusion study (thallium, 99mTc-sestamibi or 99mTc-tetrofosmin). The difference in distribution indicates viability. Although a decade ago it was regarded that this indication would account for a large number of FDG PET studies performed, It only provides a small increment of information to conventional nuclear cardiac imaging, and is not regarded as cost-effective routinely. In selected cases proof of viability can help decide if revascularisation procedures are likely to be effective.
| Fig 15:FDG PET/CT scan showing intense uptake in the oesophago-gastric primary, and metastatic disease in the celiac nodes. |  "Fig 15: Gastro-intestinal PET images - click to enlarge (970kb)") |
Mr Barrett has had oesophageal carcinoma proved on endoscopy. With equivocal CT scan for staging An FDG scan was performed (Fig. 15).
Q What does it show? How may PET help in management?
A There is intense abnormal uptake in the distal oesophagus, which is in the known oesophageal cancer . In addition, there are at least two foci in the coeliac nodes. ease. In Oesophageal cancer, PET is often of use in the preliminary staging of disease, showing distant spread more frequently than conventional imaging, and helping avoid futile surgery.
 "Fig 15: PET head and neck lesions (756kb)") |
Fig 16: FDG PET of the head and neck demonstrating tumour recurrence in bilateral upper cervical lymph nodes. |
Mr Farincs presented with a palpable cervical lymph node 1 year after treatment of primary SCC excised and treated with radiotherapy. Biopsy showed squamous cell carcinoma, but examination and conventional imaging showed no primary. A PET scan was performed. (fig 16)
Q What are the findings?
A Mr Farincs scan shows uptake in the known cervical node region indicating an FDG avid lesion, but also on the (unsuspected) opposite side. FDG PET is useful in head and neck cancers in detecting unknown primaries (in up to 50% of cases where examination and conventional imaging has failed), in staging (although for most patients CT and MRI are adequate) and particularly in monitoring response to therapy, and restaging if recurrence is suspected. No recurrence at the primary site was seen in this patient, but clearly bilateral treatment of the metastases would be needed to effect a cure.
| Fig 17:Projection FDG PET scan showing focal uptake in multiple soft tissue and visceral lesions |  "Fig 16: Multiple lesions observed with PET - click to enlarge (1.15MB)") |
Mr Breslow age 74 presented with acute GI bleeding, for which endoscopy and contrast X-rays could not determine a cause. He also had palpable left axillary lymph nodes and pleural nodules on chest X-ray. Biopsy of the axillary lesion showed malignant melanoma, but no primary was found. The PET scan was performed to determine the stage of the disease.
Q What does it show?
AThe FDG PET scan shows disseminated disease. As well as the known thoracic and left axillary disease, there are widespread subcutaneous, mediastinal and abdominal deposits of disease, which were subsequently shown to be the small bowel bleeding sites. Although this case is extreme, malignant melanoma is very FDG avid, and PET scanning can be very useful in the staging of disease prior to attempted curative treatment of apparently focalised metastases (it has no place in the initial staging of cutaneous melanoma at presentation).
| Fig 18: Ovarian cancer |  "Fig 18 - PET image of ovarian cancer - click to enlarge (999kb)") |
Q What does the Pet/CT scan show? (fig 18)
A There is active uptake in the left side of the pelvis consistent with recurrent ovarian cancer, and spread to an adjacent lymph node, but no further. PET scanning is useful for monitoring and staging ovarian, cervical and to a lesser extent, endometrial cancers.
Summary. The above examples show some of the clinical utility of FDG PET. There are many other malignancies (eg breast, thyroid, mesothelioma, GI stromal tumours) as well as some benign conditions (localisation of infection/inflammation) in which this technology has clinical value.
