Patterns of uptake of prostate-specific membrane antigen (PSMA)-targeted ¹⁸F-DCFPyL in peripheral ganglia

Recently, PET radiotracers targeting prostate-specific membrane antigen (PSMA), labeled with either ⁶⁸Ga or ¹⁸F, have demonstrated favorable results for imaging men with prostate cancer (PCa) in a variety of clinical contexts [1‐3]. Moreover, the potential utility of imaging non-prostate malignancies such as renal cell carcinoma (RCC) has begun to be more widely reported [4]. Compared to the more commonly used ⁶⁸Ga-labeled PSMA-targeted agents, the ¹⁸F-labeled PSMA-targeted radioligand ¹⁸F-DCFPyL possesses the inherent advantages of a longer physical half-life, lower positron energy, and higher positron yield, and there have also been suggestions of a higher detection rate for sites of disease as well as an increased tumor-to-background ratio [5].

Regarding the biodistribution of PSMA-targeted agents, the variability of ¹⁸F-DCFPyL uptake in several solid organs was recently assessed and demonstrated a visually homogenous uptake in the normal liver along with intrinsic variability even lower than 2-deoxy-2-[¹⁸F]fluoro-d-glucose (¹⁸F-FDG). Uptake was also noted in the lacrimal glands, salivary glands, spleen, kidneys, and small bowel [6]. ⁶⁸Ga-PSMA-HBED-CC, the most commonly used of the ⁶⁸Ga-labeled PSMA-targeted radiotracers, parallels the biodistribution of ¹⁸F-DCFPyL, with focal uptake in all the same organs and with both radiotracers having the highest uptake in the kidneys [6]. The similar biodistributions of these PSMA-targeted agents suggest that normal variant sites of uptake and potential interpretive pitfalls will be similar between these compounds. Indeed, a number of potential false-positive findings have been described that the interpreting imaging specialist should be aware of while analyzing ¹⁸F-DCFPyL or ⁶⁸Ga-labeled PSMA-targeted PET scans, including increased radiotracer accumulation in various benign entities (e.g., in adrenal or thyroid adenomas as well as in Paget’s disease [7‐9]).

Interestingly, PSMA expression has been described in nervous tissue, where this protein is known as glutamate carboxypeptidase II or N-acetylated-alpha-linked acidic dipeptidase (NAALADase). In fact, PSMA has been recognized as a potential therapeutic target in several neurological disorders [10, 11]. PSMA-targeted PET radiotracer uptake has also been seen in sympathetic chain and ganglion structures and should be considered physiologic rather than pathologic, particularly in the celiac and stellate ganglia [12]. To further investigate the pattern of PSMA-targeted radiotracer uptake within ganglia on a larger scale, we performed a qualitative and quantitative analysis of the peripheral ganglia of patients with PCa and RCC who were imaged with ¹⁸F-DCFPyL PET/CT on one of several prospective protocols evaluating this radiotracer. We would anticipate that the results of this study would be applicable to other PSMA-targeted radiotracers.

A total of 76 PCa patients with a mean age of 64 ± 7.2 years (range 47–81 years) and 22 RCC patients with a mean age of 57.8 ± 10.1 (range 34–73 years) were included in our analysis. The majority of the subjects were of white race for both the PCa (n = 65, 85.5%) and the RCC (n = 21, 95.5%) cohort. The clinical indication for imaging included preoperative PCa staging (18/76, 23.7%) and evaluation of recurrent/metastatic disease (58/76, 76.3%). For the RCC patients, similar indications were noted with preoperative staging in 6/22 (27.3%) and recurrent/metastatic disease evaluation in 16/22 (72.7%).

The present study describes the uptake patterns in peripheral ganglia, which can act as potential pitfalls when clinically interpreting ¹⁸F-DCFPyL PET/CT scans for both PCa and RCC. There was a general trend with a descending frequency of radiotracer accumulation in lumbar, cervical, stellate, celiac, and sacral ganglia. An inexperienced clinical reader could identify uptake in these physiological structures as potential sites of metastatic disease, although many of the peripheral ganglia that have been observed to have uptake are somewhat separated anatomically from typical lymph nodes that become involved with metastatic disease (the most clear exception being the celiac ganglia). Additionally, the cervical, lumbar, and sacral ganglia could potentially be mistaken for bone metastatic disease, particularly if there is slight misregistration between the PET and CT acquisitions or if the uptake is distinctly unilateral.

Generally, the stellate ganglion can also be easily identified on anatomical imaging and this was a common site of uptake in our study (65.8% in PCa) [14]. The ganglia most likely to be misinterpreted as disease-involved lymph nodes are the celiac, as described in a manuscript with extensive pathologic correlation by Krohn and coworkers who were utilizing the PSMA-targeted agent ⁶⁸Ga-PMSA-HBED [12]. Recently, using the same radiotracer, Kanthan et al. reported similar results, with up to 81% positive uptake findings in the celiac and 74% in the stellate ganglia [15]. In the present study, we evaluated the PSMA-targeted ligand uptake across all peripheral ganglia, both in RCC and PCa patients using ¹⁸F-DCFPyL. Compared to the above-mentioned investigations, our number of positive findings was lower in the celiac (59.2%) and stellate ganglia (65.8%). This may be due to a variety of factors including potential improved spatial/contrast resolution of an ¹⁸F-labeled radiotracer [16] or perhaps the different underlying chemical structures of the radiotracers which could profoundly impact localization in a primarily hydrophobic environment such as a ganglion [5, 17]. Moreover, the study population of our cohort was almost 10 years younger than the populations in the studies by Krohn [12] and Kanthan [15]. In a study of more than 7400 participants, Steiber and coworkers concluded that the average physical health in an elder population declines age-dependently [18]. Keeping in mind that physical inactivity is an important cause of most chronic diseases as well as playing a role in pain perception [19], our “younger” population included in the current study might have suffered from less biological chronic disease/pain-associated sensation of the celiac ganglia.

Investigating lumbar DRG by 3D magnetic resonance imaging in healthy volunteers, 90% of the DRG showed an intermediate signal intensity, which is in line with the frequency of uptake in our PCa (72.4%) and RCC (90.9%) cohorts [20]. Hence, while interpreting ¹⁸F-DCFPyL PET, a clinical reader should keep in mind that physiological uptake in the lumbar region is a frequent phenomenon which could be falsely mistaken as a metastatic site, similar to potential false-positive findings in the celiac ganglia [12]. The same tendency of gradually increasing findings of DRG from L1 to L5 [entire cohort: L2, 20/98 (20.4%) vs. L4, 63/98 (64.3%)], the more frequent occurrence of bilateral ganglia in L4 (entire cohort: 41/63, 65.1%) as well as the fact that the right-left difference in PSMA-uptake reached no significance, could also be observed in the present study [20, 21].

This study has several limitations. First, given its retrospective nature, further confirmatory studies are warranted. Second, no histologic proof of the obtained PET results can be given in light of the benign nature and characteristic locations of ganglia. Moreover, ganglia uptake may be underestimated as partial volume effects have to be considered in small structures less than 15 mm.

Clinical readers should be conscious of potential false-positive findings while interpreting PSMA-targeted PET, and uptake in the lumbar, cervical, stellate and celiac ganglia could be potentially misinterpreted as metastatic lesions. We provide a description of the patterns of ¹⁸F-DCFPyL uptake in peripheral ganglia in a large and varied patient cohort. Future research should aim to define the mechanisms underlying the variability of PSMA-targeted radiotracer uptake by peripheral ganglia.