Assessment of malignancy and PSMA expression of uncertain bone foci in [¹⁸F]PSMA-1007 PET/CT for prostate cancer—a single-centre experience of PET-guided biopsies

First introduced clinically in 2011 [1], combined positron emission and computed tomography (PET/CT) using the PSMA-radioligand [⁶⁸ Ga]Ga-PSMA-11 has established itself as the gold standard for the imaging of recurrent PC. More recently, [¹⁸F]-radiolabelled PSMA ligands have been introduced and have a number of potential advantages when compared to [⁶⁸ Ga] [2]. Amongst these tracers is [¹⁸F]PSMA-1007, for which previous studies suggest a higher PET-positivity rate [3]. However, there are a number of reports of high rates (in up to half of all patients) of unspecific or equivocal bone foci (UBU), which cannot be clearly classified as benign or malignant [4, 5]. These can often pose diagnostic conundrums and place the patient at risk of being incorrectly staged; this could adversely impact treatment outcomes or might require further diagnostic workup [6]. Furthermore, with increasingly sensitive digital and ultra-long field-of-view PET/CT systems available, this problem may increase yet further in importance [5, 7‐9].

Despite widespread implementation, including at our own centre, there is only limited evidence regarding the diagnostic accuracy of [¹⁸F]PSMA-1007, particularly for bone foci. The available literature seldom reports any comparative imaging data or uses a reference standard to confirm equivocal PET findings [3], and thus represents an urgently unmet need in evidence-based imaging for PC. Although follow-up data for a small cohort of patients with UBU in primary PC are reported [10], no similar data with a histopathological reference standard has been published for UBU in a biochemically recurrent setting, where histological confirmation is less readily available. PET-guided biopsies are a useful and minimally invasive method of obtaining material for biopsy, particularly where in the absence of morphological findings in the CT, conventional CT-guided biopsy cannot be performed [11]. In this short communication, we share our experiences and the results of PET-guided biopsies of UBU in [¹⁸F]PSMA-1007 PET/CT.

The outcomes of each biopsy are as detailed in Table 1. A total of 11 UBU in 10 patients were biopsied. None of the UBU presented with a morphological correlate in the CT scan. All biopsies were clinically well tolerated.

In summary, 1/11 (9.1%, 95% confidence interval (CI) 1.6–37.7%) of the foci biopsied was confirmed as a bone metastasis of PC with intense PSMA expression at IHC, while 10/11 (90.9%, 95% CI 62.2–98.4%) foci were revealed to be unremarkable bone tissue without evidence of PSMA expression at IHC. Example foci shown in the PET/CT and the histopathology results are presented in Fig. 1. Histopathology for the nonmalignant UBU was unremarkable, with no indication of a secondary bone pathology or metastasis of a second malignancy.

All foci with a radiotracer uptake (local relapse, lymph nodes, bone foci, etc.) were assessed as being at high risk of malignancy, equivocal or low risk of malignancy by two experienced readers in consensus as described above. Amongst all foci examined, those judged to be at high risk of malignancy (n = 17) had higher uptake of [¹⁸F]PSMA-1007 than those judged to be equivocal (n = 20) or low risk (n = 20): SUVmean high risk: 12.2 ± 7.4, equivocal: 4.3 ± 1.6, low risk: 3.5 ± 1.3; SUVmax high risk: 18.9 ± 12.1, equivocal: 6.7 ± 2.1, low risk: 7.7 ± 10.6.

Amongst those bone foci, which were assessed by biopsy, eight were visually classified as being at high risk of malignancy in the PET/CT (SUVmean 12.0 ± 8.1; SUVmax 18.8 ± 13.1), three as equivocal (SUVmean 4.6 ± 2.1; SUVmax 7.2 ± 3.0), and zero as low risk. None of the bone foci presented with a CT correlate. The single focus demonstrated to be a PC metastasis showed intensive uptake (SUVmean 29.2, SUVmax 47). However, as can readily be appreciated from Fig. 2, substantial overlap in uptake values occurred between foci demonstrated to be benign in origin and those judged to be at high risk of malignancy. Clinical follow-up was performed for all patients. Six patients were lost to follow-up despite all reasonable efforts to contact the patients’ physicians. For the four patients where follow-up was available, no conclusive standard of truth was available, for example for three patients despite clear fall in PSA post-stereotactic radiotherapy with the UBU outside the radiation volume, the PSA remained measurable.

We present the first published cohort of PET-guided biopsies for confirmation or refutation of PC in UBU for [¹⁸F]PSMA-1007 in a series of 10 patients. We found that only one out of eleven foci biopsied was a metastasis of PC. Similar results were reported in a series of bone foci with follow-up, albeit in a small cohort of patients (n = 15) with primary PC [10]. Nevertheless, we interpret these studies with small cohorts with caution; larger and better-powered studies are required to estimate the true scale of the problem. Moreover, the number of reports of invasive measures to clarify UBU, including rib resection [14, 15], suggest that occasionally, diagnostic dilemmas can occur, which warrant highly invasive measures and are a clinically relevant issue. Although SUV cutoff values have been advanced as a means of differentiating between benign and malignant foci [4], we find in our series of biopsies a substantial overlap between foci judged to be clinically at high risk and with high tracer avidity, yet with benign histology. Moreover, Grünig et al. find that even with follow-up, 43% of UBU remain unclear, further demonstrating that there is currently no satisfactory method to differentiate reliably between UBU in [¹⁸F]PSMA-1007 PET/CT [5]. In contrast to the more established [⁶⁸ Ga]Ga-PSMA-11, where prospective diagnostic accuracy studies have been performed [16], only limited data are available for [¹⁸F]PSMA-1007 with only preliminary observations in small cohorts [17], in mixed cohorts of primary and recurrent PC, [18] thereby with limited interpretability, or without any verification of positive findings [19, 20]. Further studies are urgently required to determine the true diagnostic accuracy of [¹⁸F]PSMA-1007, especially for bone foci.

Interestingly, despite intensive avidity for [¹⁸F]PSMA-1007 and that a substantial proportion of the foci biopsied were judged clinically to be at high risk of malignancy, no evidence of PSMA expression could be demonstrated at IHC. Previous reports of nonspecific salivary gland uptake posit a non-PSMA-related uptake mechanism [21]. The lack of IHC PSMA expression, and lack of histopathological evidence for benign, inflammatory, or other malignant entities, suggests a potential non-PSMA-receptor-mediated uptake mechanism for UBU in [¹⁸F]PSMA-1007 PET/CT; further studies are needed to elucidate the true mechanism for this, which remains unclear. For example, variation in molar activity has been demonstrated to influence the biodistribution of some PSMA-radioligands [22]. Quality control of the GMP manufactured radiopharmaceutical and the high frequency with which UBU are observed in other centres makes a local radiochemical purity problem unlikely [4, 5].

There was a lack of histopathological evidence indicative of PC or other inflammatory or neoplastic processes suggestive of a non-PC malignancy. Although PSMA-negative PC can occur in a minority of patients [23], this cannot explain the discordance between PSMA PET/CT and IHC findings and points towards an as yet unclarified issue with the radiopharmaceutical. Noting the abundance of reports of UBU and being cognisant of their potential adverse clinical impact, further studies are necessary to understand better this phenomenon and the limitations of this tracer. Meanwhile, we find PET biopsy to be a useful and minimally invasive method of clarifying UBU, particularly where, in the absence of a CT correlate, traditional CT-guided biopsy is not possible and where clinical interpretation of imaging findings or SUV cannot reliably differentiate between benign and malignant UBU. All biopsies could either confirm or refute clinically suspicious foci, enabling more accurate staging.

This short communication with clinical data is primarily limited by its small cohort size as well as the necessarily undefined selection criteria for patients referred for a biopsy on clinical grounds. A further weakness was the lack of useful data in the follow-up period, which could clarify the non-biopsied UBU. Future systematic studies, including biopsies of low-risk foci, are warranted to evaluate better the true scale of this problem and to evaluate what the true incidence of malignancy is amongst UBU in [¹⁸F]PSMA-1007 PET/CT.

UBU are common in [¹⁸F]PSMA-1007 PET/CT. In our small cohort, one of eleven biopsies represented a true metastasis. For those confirmed as benign, no IHC evidence of PSMA expression was found, suggesting a non-PSMA-receptor-mediated mechanism for focal bone uptake, the cause of which remains unclear. Readers must interpret focal bone uptakes of [¹⁸F]PSMA-1007 with caution in order to reduce the risk of erroneous staging and treatment of patients, particularly where our cohort suggests that reliance on interpretation of SUV or clinical characteristics does not reliably differentiate between benign and malignant foci. We endorse the use of PET-guided biopsy as a useful and minimally invasive option to clarify focal bone uptakes of [¹⁸F]PSMA-1007, particularly where the lack of CT correlate makes CT-guided biopsy impossible and where the subsequent treatment is critically dependent on the characterization of the bone lesion.