The emergence of PET/CT: Engineering, innovation, and usage (2022)

The first prototype combined positron emission tomography/x-ray computed tomography (PET/CT) scanner was built at the University of Pittsburgh Medical Center in 1998. This had a major impact on nuclear medicine and its role in radiology. It is possible to look at the emergence of PET/CT in three ways: engineering, innovation, and usage. The role of medical physics was present in all of these. The high signal-to-noise ratio of many solid cancers imaged with 18F-FDG PET leads to advantages in the conspicuity of tumors compared to other modalities. However, it was recognized in the early 1990s1 that the location could be difficult to precisely determine due to the relatively low resolution and high noise inherent in PET imaging as compared to CT or magnetic resonance imaging (MRI). Small shifts in the estimated location, for example, if a lesion is separate from, or invading into, an organ or tissue boundary, can cause major changes in the diagnosis, staging, treatment decisions, and expected outcomes. For this reason, considerable attention was focused on the development of image registration methods where the anatomic detail of CT or MRI was fused with the functional information uniquely available from PET. Although this technique can be used successfully in the brain, it is logistically challenging in the body for multiple reasons, including differences in relative anatomic positions between PET and CT scans from external positioning differences, differences in bowel gas distribution, changes in hydration, and other reasons. During this time in the early 1990s, David Townsend was working at the University Hospital Geneva in Switzerland in collaboration with CTI Inc. of Knoxville, an early manufacturer of PET scanners, and was developing a prototype of a low-cost PET scanner called the Advanced Rotating Tomograph (ART)2 (Figure 1). The ART scanner reduced costs by having only two partial segments of the detector ring. The two opposed banks of detectors covering approximately one-third of a conventional full ring, which rotated to acquire tomographic data as illustrated in Figure 1. The so-called “fully-3D” acquisition, that is, without slice-separating septa, gave this tomograph sensitivity comparable to a conventional full ring tomograph operated in 2D mode. The transition from 2D imaging to higher sensitivity, but more complex, fully-3D imaging in PET was another transition that was underway during this period. The 3D-Reprojection (3DRP) algorithm3 became the industry standard in the mid-1990s, and also led to my visiting David Townsend in Geneva to see the ART scanner, which implemented the 3DRP algorithm. I visited independently using my own funds while I was still a graduate student at the University of Pennsylvania. My PhD advisor, Joel Karp, later graciously agreed to reimburse my expenses. In retrospect, I would be challenged to supervise the graduate student that I once was, and I am grateful for the flexibility and patience that Joel had, in addition to his mentorship in research. These interactions eventually led to my first job as a medical physicist with David Townsend when he relocated to the University of Pittsburgh. Prior to departing University Hospital Geneva, an encounter that David Townsend later related was that when he was showing the ART scanner with the covers off to another faculty member, they remarked that there was enough space between the PET detector blocks to install a CT scanner. At the University of Pittsburgh, we, along with our then graduate student Thomas Beyer, submitted an R01 grant to NIH in 1995 to build a prototype rotating PET/CT. On the second try, the grant was funded, and while the R01 grant was not enough to pay for all the costs, it was enough to start the project in partnership with CTI. Figure 1 shows one of the early concept drawings. The PET and CT configuration turned out to be impractical for two major reasons discussed below. However, the figure was a useful conceptual tool for communicating the primary concept as well as some secondary issues. With the help of CTI, the Pittsburgh team bought a Siemens SOMATOM AR.SP CT scanner, a lower cost helical scanner that had been introduced in 1994. In a fortuitous manner, both the ART PET and the AR.SP CT scanners had been designed to rotate at 0.5 rpm. At the CTI facility in Knoxville, the engineering team worked though the numerous engineering issues of combining the ART and AR.SP scanners. An early realization was that while there was space for other components on the ART gantry, the AR.SP gantry was completely full, which would have been obvious to those experienced with CT hardware. The solution was to attach the ART detectors to the back of the AR.SP gantry, which lead to a 60 cm axial offset between the PET and CT subsystems. In other words, while the scanners were co-axial, they were not co-planar as implied by the original concept (Figure 1). While disappointing, this turned out to be fortuitous, as the x-ray photon flux was approximately 107 times higher than what the PET detectors were designed for. The reduction of photon flux from the separation helped reduce PET detector afterglow and other issues. This separation of the imaging planes is still present in modern commercial PET/CT scanners, but with the PET and CT subsystems on independent gantries. Another major change in modern scanners is that the PET subsystems are all higher sensitivity full-ring scanners that do not rotate. While there was never any doubt that a functional dual-modality system could be built, the amount of engineering advances and refinements that were needed cannot be overemphasized. Examples of these include providing accurate co-axial alignment of the PET, CT, and couch subsystems to less than a millimeter, managing the extended axial motion of the couch (i.e., the patient handling system) through the PET and CT scanners, interconnecting the PET and CT data acquisition and image reconstruction systems, management of the thermal/power/data requirements, creating efficient multimodality workflows, and many others. These are in addition to the already challenging requirements for the individual PET and CT subsystems. It has been a privilege to witness the often unsung but dramatic engineering advancements that have occurred since the development of the prototype PET/CT scanner. The main innovation of PET/CT imaging was the near-simultaneous PET and CT imaging of a patient with essentially the same physical alignment in both scans. This directly addressed the requirements for accurate anatomical localization of the 18F-FDG radiotracer with diagnostic CT images. A key technical innovation was to use the CT image for attenuation correction of the PET data, which is required for quantitative accuracy. PET images with correction for the 511 keV photon attenuation are now taken for granted. However, even in late 1990s, there was considerable debate about the use of attenuation correction methods, which were largely based on systems of orbiting rods containing the positron emitter 68Ge/68Ga. The transmission imaging methods behaved like a monoenergetic CT scanner, as Hounsfield originally envisaged. However, these 511 keV transmission imaging methods could only operate at very low photon flux rates due to deadtime in the near-side PET detector. Consequently, PET scans were typically doubled in duration due to the need for an extended transmission scan, with an increased potential for complex artifacts due to patient motion between, or during, the PET emission and transmission scans. Even if there were no motion artifacts, the attenuation-corrected PET images had high levels of heavily correlated noise as compared to the images without attenuation correction.4 A key insight was the recognition that normalizing the linear attenuation coefficient by density (called the mass attenuation coefficient) at 511 keV, one scale factor could be used for all low-Z materials, such as soft tissues or air. This was a result of the dominant interaction with photons being Compton scatter, which depends only on electron density in the energy range that includes X-ray and annihilation photons as shown in Figure 2 (left). For higher-Z materials, this would also be dependent on the elemental composition. However, in CT imaging, higher-Z materials typically only include bone and contrast agents, which can be identified by the Hounsfield unit values in the CT images, and a second scale factor applied to those voxels as needed. By this means, an aligned CT image could be converted to a PET transmission image with essentially no noise (compared to the PET emission image) and low bias. The publication of this method was in Medical Physics.5 There were other technical details that needed (or still need) solutions in CT-based attenuation correction (Figure 2, Right): Resolution matching between the PET and CT images; accounting for the energy spectra differences of different CT acquisitions; positional differences between PET and CT data due to respiratory, cardiac, and other motions. However, the similarity in the physics of PET and CT imaging was the key enabler for CT-based attenuation correction. The use of CT-based attenuation correction provided multiple benefits. The most obvious were the substantial reductions in scan duration and PET image noise. There was a third benefit, which was avoiding the challenges with the so-called post-injection transmission scanning. A typical PET protocol calls for an injection of 18F-FDG and then an uptake period (typically 60 min) for the radiotracer to be biodistributed, ideally accumulating in tumors and washing out of normal tissues. With 511 keV transmission imaging using a 68Ge/68Ga source, there was contamination of the 511 keV transmission photon signal from the endogenous 511 keV emitting 18F-FDG. This bias could be corrected for, but the corrections invariably added bias, noise, and complexity. The high photon flux of CT imaging, however, obviates the impact of the contamination from the endogenous 511 keV signal. Other innovations arose from, or were driven by, the PET/CT prototype. These included the development of the first clinically used PET-CT image fusion display package, called “PETCT_viewer.” This used the IDL language and was based on the Clinical Applications Programming Package (CAPP) used by CTI in their PET display software. PETCT-viewer was widely distributed as an open-source package from 1998 to 2001, and in one case was mistakenly (and amusingly) included as a requirement in the purchase order of a PET scanner unconnected with the University of Pittsburgh. The prototype PET/CT system was installed at the University of Pittsburgh and approximately 200 oncology patients were imaged with 18F-FDG after the system became operational in June of 1998.6 The results garnered considerable attention, including being listed as a 2000 “Innovation of the Year” by Time magazine and the “Image of the Year” award at the Society of Nuclear Medicine annual meeting. Consequently, there was attention paid by both institutions looking to buy new PET scanners and scanner manufacturers. Separately during that period, Medicare announced that it would start reimbursing for the use of 18F-FDG PET scans for some indications of cancer, starting with lung cancer. This led to a remarkable period, illustrated in Figure 3, where the number of clinical PET scans increased exponentially, and the number of PET/CT scanners went from 0% of the market to over 90% over a 4-year period, a rare example of a disruptive technology in medical imaging. This disruption extended in several directions, including the need to manage combined radiology and nuclear medicine workflows in the imaging suites by technologists, reading-room physicians, billing coders, and referral patterns with oncologists. Speculating on the causes for this rapid adoption and growth of PET/CT in the modern era of evidence-based medicine and comparative effectiveness analysis, there are a few factors that played a role: During the development of the prototype PET/CT scanner, several visiting radiologists and nuclear medicine physicians stated that the value of combined PET/CT was perhaps the increased confidence in the interpretation of the PET images, which would lead to a reduction in the reading time. This was in addition to the reduction in the patient scan duration by using CT-based attenuation correction as discussed above. With the rapid growth in imaging procedures, competition between imaging centers was perhaps also a factor, as it was for the rapid adoption of 64-slice CT imaging that occurred several years later. Nonetheless, evidence did follow several years later showing that combined PET/CT imaging was superior to PET or CT only imaging for many tasks in cancer imaging.7 It should be noted that improvements in PET/CT technology for imaging of cancer and other diseases continue to occur, with considerable excitement now for extended axial-field of view PET systems leading to much higher sensitivity. These, coupled with new algorithms for image reconstruction and quantitative corrections, have led to dramatic improvements in image signal-to-noise ratio. The engineering, innovation, and usage of PETCT that led to (and resulted from) the prototype scanner remains a remarkable event in the history of medical physics. The dramatic changes were due to multiple factors, including the parallel technologies of the ART PET scanner and the AR.SP CT scanner, the value of combining anatomical and functional imaging of cancer, the market and societal forces, the people involved, and the central role of medical physics. I would like to thank the many colleagues and mentors that I interacted with during this project. In addition to those named above, I would like to mention Gerd Muellehner, Edward Hoffman, Michel Defrise, Rolf Clackdoyle, James Colsher, Charles Stearns, Mike Casey, Carolyn Meltzer, Claude Comtat, Bruce Hasegawa, Carole Lartizien, Christian Michel, and David Brasse. The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.