PET Oncologic Imaging:

[18]F-fluorodeoxyglucose (FDG) Imaging:

The transport of glucose into a cell is mediated by a family of structurally related glucose transporter proteins. One of the biochemical characteristics of malignant cells in an enhanced rate of glucose metabolism due to increased number of these cell surface glucose transporter proteins and increased intracellular enzyme levels of hexokinase and phosphofructokinase which promote glycolysis. This enhanced glycolytic rate of malignant cells facilitates their detection utilizing PET FDG imaging.

Several processes determine FDG uptake in tumor cells. Of major importance is the integrity of the vascular network that is necessary for supply of nutrients to the cell. FDG enters the cells by the same facilitated transport mechanism as glucose. The most common glucose transporters expressed on the cell membrane are Glut-1 which are insulin independent. Once inside the cell, FDG is phosphorylated by hexokinase into FDG-6-phosphate. FDG-6-phosphate does not enter into further metabolism and accumulates intracellularly. Reduced levels of glucose-6-phosphatase within tumor cells compared to normal cells permit longer intracellular retention of FDG-6-phosphate. The signal derived from tumors represents an average of the FDG uptake throughout the lesion. In vitro studies have shown that FDG uptake may be determined mainly by the number of viable tumor cells within a lesion (tumor cell density). Non-tumoral tissue such as necrotic and fibrotic tissue may reduce tracer uptake. Increased cell proliferation in tumors (assessed by the mitotic rate) also results in increased glucose utilization. Tumor hypoxia also increases FDG uptake through hypoxia-inducible factor-1-alfa which upregulates Glut-1 receptors.. The bottomline is that FDG accumulation within a tumor is likely related to a complex interaction between the cellular energy demand and the tumoral microenvironment.

Unfortunately, FDG is not a cancer specific agent and its uptake has been described in a number of inflammatory lesions including sarcoid, tuberculosis, fungal infection, and cerebral abscess. The increased accumulation is probably related to a markedly increased rate of glycolysis within activated inflammatory cells. Delayed or dual phase imaging may help to differentiate between benign and malignant processes. A persistent or increased level of FDG accumulation within a lesion on delayed imaging is indicative of a malignant process.

One other drawback of PET imaging is the underestimation of metabolic activity in tumors that are smaller than two times the spatial resolution of the scanner (partial volume effect) - however, using modern PET scanners, objects that measure as small as 5 mm can be visualized. Assessment for malignancy and metastatic disease with PET FDG imaging is improved when supplemented by CT images .

FDG imaging is performed in the fasting state to minimize competitive inhibition of FDG uptake by glucose.. A 4 hour fast is recommended prior to initiation of the PET FDG study. A 12 hour fast may decrease accumulation by the myocardium and improve detection of mediastinal metastases in cases of lung or breast cancer. If there is a possibility of an elevated serum glucose level, a serum glucose level is obtained prior to FDG administration. FDG uptake is significantly influenced by plasma glucose levels and uptake will be decreased when plasma glucose levels are elevated (elevated serum glucose levels can result in decreased FDG accumulation within the tumors).. If the glucose level is higher than 150-200 mg/dL, the study should be delayed until the glucose level is under 200 mg/dL. Administering insulin at the same time as FDG should be avoided because it tends to increase accumulation in skeletal muscle and thus less FDG is available for accumulation in tumors. In patients with diabetes, blood sugar control should be achieved with oral hypoglycemic agents or insulin (not administered near the time of FDG administration).

FDG PET scans are performed approximately 60 minutes following the intravenous injection of 10 to 20 mCi of FDG and usually require about 1 hour to acquire.

The normal distribution for FDG includes:

1- The cortex of the brain- there is generally very intense tracer uptake in the brain because the brains only energy source is glucose. The total uptake in the brain is approximately 6% of the injected dose. Metastatic CNS lesions generally have activity similar to gray matter. During whole body scanning for the evaluation of patients with primary malignancy, unsuspected CNS metastases are detected in less than 1% of patients. Because FDG PET imaging detects few clinically relavant lesions in this patient population, it should not be performed routinely.

2- Myocardium- in the post-prandial state, there is marked cardiac activity. Little myocardial activity is generally noted in the fasting state as the myocardium preferentially utilizes fatty acids for energy generation. However, uptake can be variable as even in the fasting state, glucose can still account for 30-40% of the energy derived from oxidative metabolism..

3- Renal/Urinary bladder- due to renal excretion of the agent. Hydration and frequent voiding promote diuresis and help to decrease the radiation dose to the genitourinary tract.

4- Liver- faint, heterogeneous activity is common. It is possible for both liver metastases and treated liver metastases to have liver-equivalent activity- as a result, such lesions cannot be reliably identified by PET imaging.

5- Muscular activity- exercise should be avoided on the day of scanning to avoid muscle uptake. Note: Muscles of mastication or larynx can accumulate tracer if eating or talking. Hyperventilation may induce uptake in the diaphragm and stress-induced muscle tension is often seen in the trapezius and paraspinal muscles.. Benzodiazepines may be used to decrease paraspinal and posterior cervical muscle uptake in tense patients.

6- Gastrointestinal tract- variable activity can be seen in the GI tract- partly due to smooth muscle activity. Cecal uptake may be prominent and the stomach is usually faintly seen (but uptake can be intense). There can be normal mild FDG activity in the esophagus possibly due to swallowed saliva or smooth muscle metabolism and this can potentially obscure subtle lesions.. Esophagitis in the distal esophagus is also a common cause of tracer accumulation. There is usually uptake in the lymphoid tissue of Waldeyer's ring. FDG accumulation can often occur in segments or large sections of the colon after colonoscopy- possibly due to a non-specific inflamation.

7- Thymus: Normally, physiologic uptake of FDG in the thymus disappears in adolescence in conjunction with involution of the thymus. Thymic uptake can be present in children and in patients with thymic hyperplasia (seen in up to 16% of patients) following chemotherapy. Thymic enlargement can persist for up to 6 months following completion of chemotherapy. Thymic activity is usually "V" shaped (bilobed) and generally not very intense. FDG accumulation in the thymus suggests pathology when it does not have a typical triangular shape or if the activity is very intense. Not all children will have visible thymic activity on FDG imaging.

8- Bone marrow- faint activity is generally identified within the bone marrow. The accumulation is generally homogeneous and has SUV ratios between 0.7 to 1.3. Increased bone marrow activity can be seen with bone marrow recovery following chemotherapy, but this usually resolves by one month post-therapy. Treatment with granulocyte stimulating factor can also produce diffuse skeletal FDG accumulation. In an animal model following XRT, the irradiated bone marrow shows a significant increase in FDG accumulation over baseline on day 1, a significant decrease on day 9, and a return to normal between 18 and 30 days.

9- Thyroid- thyroid uptake can occur in association with thyroiditis or Graves' disease. Focal thyroid uptake can occur with autonomously functioning thyroid nodules and thyroid malignancies.

10- Lymph nodes- nodal uptake can occur if the agent extravasates into the soft tissues at the site of injection (always inject in arm opposite primary lesion). Lymphoid tissue can also demonstrate significant uptake- particularly the tonsils and adenoids.

11- Gonads/Uterus- male gonadal activity can be seen and is quite variable. Accumulation can be seen in the uterus during menstruation.

12- Degenerative joint disease and degenerative disk disease can be associated with increased tracer accumulation

13- Vascular activity- in scans not corrected for transmission, vascular activity in the large vessels in the thighs and pelvis can be seen in about 80% of patients.

14- Breasts- variable uptake can be seen within glandular tissue in premenopausal women or women on hormone replacement therapy. High uptake of FDG can be seen in the lactating breast due to intracellular trapping within active glandular tissue. There is low excretion of FDG into breast milk and the estimated cumulative dose to a breast fed infant is approximately 0.085 mSv (well below the 1 mSv recommended for cessation of breast-feeding).