Focal unspecific bone uptake on [¹⁸F]-PSMA-1007 PET: a multicenter retrospective evaluation of the distribution, frequency, and quantitative parameters of a potential pitfall in prostate cancer imaging

Positron emission tomography (PET), combined with either computer tomography (CT) or magnetic resonance imaging (MRI), utilizing radiotracers that bind to prostate-specific membrane antigen (PSMA) is an excellent diagnostic tool for prostate cancer imaging. In the past few years, PSMA-PET has evolved to become the leading advanced imaging modality, especially for patients with early biochemical recurrence (BCR) [1, 2]. In various studies, PSMA-PET/CT has shown better detection efficacy in early BCR than MRI, CT, conventional imaging [3‐6], or choline-labeled PET ligands [7], and showed substantial impact on management [8]. Moreover, the examination is gaining increasing importance for the initial staging of intermediate and high-risk prostate cancer [9‐14].

Several PSMA ligands are available, radiolabeled with currently primary two different positron-emitting isotopes: gallium-68 [⁶⁸ Ga] and fluorine-18 [¹⁸F].The most commonly used PSMA agent in Europe was initially [⁶⁸ Ga]-PSMA-11, with well-established application for cancer localization in early BCR, with high detection rates, and an impact on management following 60% of scans [15]. In the USA, [⁶⁸ Ga]-PSMA-11 was the first prostate cancer PET tracer to be approved in December 2020 [16]. More recently, [¹⁸F]-PSMA ligands have become more available, replacing [⁶⁸ Ga]-PSMA ligands. The [¹⁸F]-labeled DCFPyL showed promising results with high image quality and good lesion detection [17], and similar results were also observed with a new class of radiohybrid tracers (rhPSMA-7) that can be labeled with [¹⁸F] or metals such as [⁶⁸ Ga], respectively [18]. The major technical advantages of [¹⁸F]-PSMA ligands over [⁶⁸ Ga]-PSMA ligands are the longer half-life (110 min vs. 68 min) and higher production capacity, as it is produced in cyclotrons rather than generators, resulting in greater availability and fewer logistical challenges. The lower positron emission energy of [¹⁸F]-PSMA ligands than [⁶⁸ Ga]-PSMA ligands (0.6 MeV vs. 2.3 MeV) also leads to a higher image resolution in comparative phantom studies [19]. One of the candidate ligands already implemented in clinical routines in several hospitals in Switzerland is [¹⁸F]-PSMA-1007, which benefits from low background activity in the urinary tract [20], which is an important advantage in suspected local recurrence [5, 21].

However, with the greater use of [¹⁸F]-PSMA-1007, initial studies have reported a higher frequency of unclear focal uptakes than for [⁶⁸ Ga]-PSMA ligands, especially in the lymph nodes, ganglia, and bones [22]. In contrast to the nonspecific uptake in the axillary or mediastinal lymph nodes and the physiologic uptake in the ganglia, unspecific bone uptake (UBU) without morphological correlates might be interpreted as metastasis, with the potential for over-staging the patient, leading to inadequate therapy. The aim of this retrospective multicenter study was to analyze the frequency, anatomical distribution, characteristics, and influencing parameters for UBUs in [¹⁸F]-PSMA-1007 PET and to evaluate their therapeutic impact.

Our study showed a high frequency (51.4%) of UBUs in patients undergoing [¹⁸F]-PSMA-1007 PET, and this number is higher compared to previously reported unspecific findings on [⁶⁸ Ga]-PSMA-11 [21]. The first publication that reported an increased number of benign and unspecific lesions using [¹⁸F]-PSMA-1007, compared to [⁶⁸ Ga]-PSMA-11, also found a substantially higher number of unclear or likely benign findings in the bones (48% vs. 14.7%), lymph nodes (39.2% vs. 13.7%), and ganglia (66.7% vs. 11.8%) [22]. The lower positron energy with higher spatial resolution and the higher signal-to-background ratio due to the longer half-life of [¹⁸F] compared to [⁶⁸ Ga] were suggested as possible explanations for this higher incidence [22]. Immunohistochemistry studies have shown that PSMA is not only expressed in prostate tissue, but is also present in inflammatory and neovascular tissue [25, 26]. Activated granulocytes in the bone marrow might therefore also lead to focal bone marrow uptake; therefore, bone marrow islands especially in rips and extremities might be a reason for focal uptake. Furthermore, other bone changes such as fibrous dysplasia or Paget’s disease have been suggested as reason for focal bone uptake [27, 28].

Ultimately, the exact mechanism remains unclear; given that UBUs usually persist in follow-up scans, a morphological correlate seems likely. In our cohort, only three UBUs were biopsied, all of them localized in the pelvis and all diagnosed as benign (two hyperplastic bone marrow and one Paget’s disease).

In our cohort, there was no association between UBU and age, ISUP score, tumor size (T classification), or PSA level, further underlining the difficulty of interpreting the lesions. The lack of correlation between clinical parameters for tumor aggressiveness with UBU presence further supports the hypothesis that these findings are not cancer related. The most common site of UBU was in the ribs, followed by the pelvis and spine. Wang et al. analyzed the distribution of prostate cancer bone metastases based on bone scans [29] and found that patients with a low number of lesions were most likely to have metastases in the spine, followed by the pelvic bones. They also found that only 1% of patients had bone metastasis outside the spine and pelvis without also having metastasis in those regions. This reinforces the theory that singular or multiple UBUs in the ribs without coexisting suspicious lesions in the spine or pelvis are most likely benign. However, although unlikely, there are cases with solitary bone metastasis in the sternum or ribs, as shown in Fig. 2a-c. More sensitive imaging tools than bone scans might also detect more uncommon locations of bone lesions.

Bone metastasis occurs in approximately 10% of patients with newly diagnosed prostate cancer, rising to 80–90% of patients in the advanced stage [30‐32]. Therefore, accurate assessment of bone involvement has a direct impact on therapy at every stage in the course of the disease; especially in patients undergoing staging or scanning for early BCR, an M1b situation completely shifts the therapeutic approach from curative to palliative [15].

There was a wide variation of frequencies of UBUs between the different centers, ranging from 36 to 69.7%. This difference might be attributed to the higher scanner sensitivity, given that center A, at 69.7%, was the only institution with digital PET technology. Several studies have shown improvements in lesion detection with digital scanners compared to analog systems for ¹⁸F-FDG PET, possibly also leading to higher detectability of UBUs using [¹⁸F]-PSMA-1007 [33, 34]. This was suggested by Alberts et al., who reported a higher detection rate of both prostate cancer lesions and benign PSMA-avid lesions with digital than with analog systems [35]. When comparing digital PET/MR with analog PET/CT, this difference was not visible, and this could be due to the slightly reduced sensitivity of digital PET detectors in MRI scanners due to coils and the magnetic field [36]. It can therefore be assumed that, with more installations of high-end digital PET systems, the frequency of UBU in ¹⁸F-PSMA-1007 imaging will become even more challenging. We also observed a higher incidence of UBU on scan after 90 min compared to 60-min uptake time, and this could be due to an increased visibility of lesions after 90 min due to reduced background uptake.

The increase in UBU in [¹⁸F]-PSMA-1007 imaging might impair clinical decisions and could lead to an increase in follow-ups with imaging in cases of ambiguity. Due to the significantly higher number of UBUs with [¹⁸F]-PSMA-1007, the previously suggested standardized image interpretation for [⁶⁸ Ga]-PSMA-PET/CT published by Fanti et al. should not be adopted for [¹⁸F]-PSMA-1007 [37], or else the frequency of findings defined as pathological could be significantly higher, leading directly to an overdiagnosis of bone metastasis. Figure 8 shows an example of PSMA-avid bone lesions over-diagnosed as bone metastasis in [¹⁸F]-PSMA-1007 PET/MRI, with a potential impact on the patient’s primary treatment protocol.

The clinical significance of lesions is very subjective and can only be evaluated by incorporating clinical information, as well as the patient’s decision, which was beyond the scope of this retrospective study. We therefore evaluated the hypothetical impact of UBUs on patient management in the different imaging settings and tried to reflect how often UBUs actually resulted in a CP. Based on this assessment, 80 out of 179 patients with UBUs were considered to have CPs (44.7%), but despite this relatively high number, only 39 of the 179 (21.8%) had a follow-up examination. This might be partly due the high number of still-unclear results after follow-up imaging (Fig. 5).

This is a retrospective analysis with associated limitations, most important being the lack of histopathological findings for the bone lesions. Histopathological analysis of UBUs was performed in only three out of 179 patients, showing the difficulty of biopsies for lesions without morphological correlates. Imaging or clinical follow-up after radiotherapy was available only in 36 of 179 scans; therefore, 79% of scans with UBUs did not have follow-up exams, furthermore, while the differences in scanners and protocols at the different centers offer some insights into, for example, the impact of scanner technology on the incidence of UBUs, the asymmetric contributions of the different institutions may have led to a certain bias (e.g., center D having a relatively high number of UBUs (61%) despite analog detectors, but an overall low number of scans). In addition, unspecific bone lesions were selected and clinical implications interpreted subjectively, without a second reading or consensus.

Despite the abovementioned advantages of [¹⁸F]-PSMA-1007 over [⁶⁸ Ga]-PSMA-11, we found a high incidence of UBUs—which are clinically challenging—in a significant number of patients. If examinations are performed using digital PET scanners, UBUs are detected more frequently than using analog PET scanners. UBUs should be interpreted carefully to avoid over-staging.