A while ago, a PET scan report landed on my desk. It was a six-page document, detailing the methodology, the operative procedure with organ-by-organ detailed results. All in all, it was a very impressive presentation. The conclusion however after all the words suggested that the results were negative; in other words the patient so tested failed to show any abnormal activity in any of the organs.
“Good” I said and picked up the receiver and called to inform the patient, which made her happy too. But there was this lingering dark cloud turgid with contrary thought that lurked over my head. I pulled out the previous report and compared them. Hmm. There was a discrepancy in the followup diagnostic testing somewhere and I, for my patient's sake, needed to find that out.
Follow up Algorithm of patient care
Sleuthing is a strange vocation. It keeps opening new doors and closing others. The rabbit hole of progress takes you through some very deep and dark alleys.
What is PET scan?
PET stands for Positron Emission Tomography: The positron is a positively charged ion, the emission indicates a radioactive decay that is being witnessed and captured by the sensors and the tomography is the detailed radiological view of multiple planes of the human body. The single plane technology was created by Robertson and colleagues in the Brookhaven Lab in 1961. Following that Wolf and associates discovered the 18F-FDG (Fluorodeoxy-D Glucose) for use as a radiopharmaceutical as a scanned material in 1968. Abbas Alvi in University of Pennsylvania was the first to use the 18F-FDG in normal human volunteers for the first time in 1972.
Emissions: Signal to Noise Ratio
Let us focus on the emission aspect of this wonderful new technology for all its worth. A radiopharmaceutical agent is a radio-nucleotide that by virtue of their instability undergoing decay leading to gamma emissions, which are captured by the scanner. These gamma emissions from the sites that accumulate based on oxygenation needs, occur at such a rapid pace that detectors with less than 10 nanosecond rate get very poor results due to the inability to resolve the “signal to noise ratio.” Thus the results are sub-par and a lot of interpolation and guesswork is involved. While newer machines with capabilities in the 100 picoseconds will have crisp data, it will be almost like comparing the new digital OLED TV screens to the cathode ray tube of the yesteryear when these new machines come online.
18F-Fluoro Deoxy-Glucose and the Periodic Table
In the Periodic Table, Oxygen is the 8th element and is followed by Fluorine, which is number nine. So the concept of creating an 18-Fluorine from the 18-Oxygen arose initially by using electrochemical fluoridation. Nowadays this is done by means of a Cyclotron, bombarding protons at the 18-oxygen ions in a 18-Oxygen “enriched water” and with a “knockout reaction” displacing it with 18-Fluorine ions. The 18-Fluorine ions have a half-life of 109.8 minutes or under two hours.
FDG and the cell
Since the 18F-FDG is an analog of the 18-Glucose the metabolically active cells take it up for energy production. The phosphorylation of the 18F-FDG ~> 18F-FDG-6-Phosphate prevents release of the glucose out of the cell. Since 18F-FDG is missing the 2’OH (Hydroxyl group) it is also unable to be utilized in the glycolysis (glucose breakdown). This combined inability of phosphorylation and non-utilization leads to an accumulation of the 18F-FDG-6P within the cell, thus represents the glucose requirement of a functionally active cell as is seen in the normal brain and the kidney and in the “high-octane” cancer cells.
PET scan result
18F-FDG Metabolism and Excretion
The normal radioactive decay of 18F-FDG yields 18-Oxygen-deoxyglucose, which picks up an H+ from the hydronium ion in the liquid medium of the cell, thus creating an OH (hydroxyl) group and a non-radioactive trans mutated 18O-Glucose-6 Phosphate that remains in the cell, which is then metabolized through the usual pathway.
18F-FDG half life
Even though the half-life of 18F-FDG is 109.8 minutes, the disposal however is via two methods. 1) 75% is by metabolism as described above into a harmless non-radioactive metabolite and 2) 25% is via direct kidney excretion in its radioactive mode (rapid elimination prevents the half-life decay) in the form of radioactive urine excreted by the patient. However, within 24 hours (13 half-lives), the radioactivity in the patient and in any initially voided urine which may have contaminated bedding or objects after the PET exam, will have decayed to 2^−13 = 1/8192 of the initial radioactivity of the dose. So it is imperative to be careful of the radioactive waste for at least 48 hours.
Okay now that we have figured this out, let me take you deeper into the puzzle posed above in that PET scan report:
18F-FDG Half-Life and Transportation
Given the half-life of 18F-FDg is 109.8 minutes or under 2 hours, it means a facility without an in-house cyclotron to create the 18F-FDG would have to import such from another facility. That transportation time then has to be incorporated into the value of the half-life. In other words if the transport of the 18F-FDg took 2 hours then more than half of the 18F-FDg would have decayed and rendered useless, correct? So the game is to estimate into the transport system the time lag of the transportation and send a larger dose that when it reaches the facility will have enough volume and still be optimally radioactive and capable of appropriate use. This is done via specially designed and regulated transportation services. A further hitch would be the time the radiopharmaceutical agent arrives at the hospital or facility and the radiopharmaceutical-pharmacist accounts for it and then it gets transported to the patient room and is dripped through the IV infusion into the patient.
By now you have guessed my confusion of that PET scan result that I had obtained. Indeed the uptake was normal because not enough of the functional 18F-FDG remained to give a valid test. Repeating it with more stringent criteria revealed the error.
Pitfalls and other considerations in PET scanning
Another problem that sometime might happen is if there are two metastatic cancer sites in an organ. One may have cells in an active state of division, that site will necessarily uptake the majority of the 18F-FDG leaving little for the other less functionally active site and therefore the PET results may show a high intensity uptake or SUV (standardized uptake value) in the small tumor and a weak signal uptake in the larger one, even though both are malignantly active. The size of the tumors are better judged by a CT or an MRI scans and nowadays the images of the PET can be merged with the CT and the MRI for better volume delineation of the state of the human disease.
As might be obvious, a high blood sugar value will minimize the uptake of 18F-FDG since 18-F and 18-O are “kissing cousins” on the periodic table, the high limit of blood sugar has to be maintained below 180 mg/DL in order for the test to be performed accurately. Additionally an active source of infection or chronic inflammation will garner a major share of the 18F-FDG, due to the glucose needs of the infected/inflamed sites. The differentiation between the myriad issues that surround PET scanning is the purview of the physician.
PETs are PETs but they still need to be patted on the head and deloused occasionally.
An error does not become truth by reason of multiplied propagation, nor does truth become error because nobody sees it. ~ Mahatma Gandhi