The present study investigated the added value of 68Ga-PSMA-11 PET/CT in patients with newly diagnosed PCa who recently underwent BS. 68Ga-PSMA-11 PET/CT diagnosed bone metastases in 10% of patients with negative BS results, provided a firm diagnosis in 20 of 22 patients referred for 68Ga-PSMA-11 PET/CT due to equivocal BS results, and confirmed bone metastatic disease in all patients with positive BS results, but 68Ga-PSMA-11 PET/CT also identified a notable proportion of patients in whom PSMA-avid lesions in the ribs were false positive.
Pyka et al. published the first comparison of 68Ga-PSMA-11 PET/CT with BS in patients with PCa, including 37 patients at primary staging . They found a sensitivity and specificity of 68Ga-PSMA-11 PET/CT of 100% at primary staging. Likewise, Lengana et al. reported a sensitivity of 96% and specificity of 100% of 68Ga-PSMA PET/CT for the detection of bone metastases at primary staging . In the present study, the sensitivity was comparable to that found in prior studies, whereas the specificity was slightly lower than the previously reported specificity, which might be explained by the four patients with false-positive PSMA-avid uptake in the ribs.
68Ga-PSMA-11 PET/CT has previously shown an ability to detect bone metastases in a proportion of patients without bone metastases apparent on BS. Lengana et al. reported that PSMA PET/CT revealed bone metastases in 8.4% of patients with negative BS results , which is in line with the present findings in which 10% of the patients without bone metastases on BS were considered metastatic by PSMA. Among patients with bone metastases on BS, PSMA PET/CT confirmed M1 bone disease in all patients and showed more metastasis-suspected lesions than those detected by BS. These findings are in line with recent observations .
Although PSMA PET/CT was indeterminate in some cases, it provided a definitive imaging diagnosis among 96.4% of the patients in this population at the primary staging. These findings are comparable to findings in patients with biochemical recurrence after curatively intended treatment, where PSMA has been shown to provide a definite diagnosis in 99% of patients .
The fact that four patients obtained false-positive results based on PSMA PET/CT was unexpected and has not been reported in prior studies [8, 17]. In each of these four patients presenting with a total of five PSMA-avid lesions of non-prostatic origin, morphologic changes were observed in the corresponding CT images. However, biopsy ruled out bone metastases in one patient. In addition, the incorporation of a PSA < 0.1 ng/mL 12 months after radical prostatectomy served as a relatively reliable verification of non-metastatic diseases in three patients. In accordance with the BVC, PSA-negative metastatic PCa in the mentioned patients is very unlikely. The false-positive findings were likely not due to reader inexperience; two of the observers (HDZ and AAO) were highly experienced and evaluated PSMA PET/CT in numerous trials [5, 6, 17]. After we performed the blinded evaluation of the 68Ga-PSMA-11 PET/CT in the present study, a number of cases with PSMA-avid bone uptake in benign skeletal conditions were published [18,19,20,21], revealing that fibrous dysplasia in the ribs or rib fractures may be PSMA-avid. In summary, these findings emphasize the need for careful interpretation of PSMA PET/CT in rib lesions.
The strength of the present study is the consecutive inclusion of patients. Due to the unique national security number in Denmark, it was possible to perform a thorough follow-up on patients included in the study, even if the patients moved across regions within the country. In the present study, detailed follow-up data were available in most patients. A shortcoming is that histologic confirmation is rarely available in imaging studies of the bone. However, performing biopsy routinely is not ethically reasonable, and consequently, a composite endpoint (BVC) was applied in the present study. A BVC has previously been used in diagnostic studies of bone metastases, including studies comparing 68Ga-PSMA-11 PET/CT to BS [6,7,8, 15]. One of the limitations of the BVC is that the index test itself often plays a key role in the definition of the BVC, as the interpretation of a new and promising method might be unreasonably trusted in the final conclusion based on the BVC. In addition, the extent of clinical, imaging, and biochemical data available for the BVC have seldom been reported. Here, we included detailed information for a minimum of 12 months for all patients with at least one lesion according to either BS or PSMA. A minority of patients did not have data allowing for a definitive conclusion of BVC. For these reasons, it is imperative to consider the intrinsic verification bias when using a BVC. For the present study, the limitations are reflected in the sensitivity of 1.00, which is likely to be overestimated.
Patients were excluded if they had received any kind of treatment for PCa prior to BS and 68Ga-PSMA-11 PET/CT, which indicates that the scans were not influenced by the negative effects of ADT on PSMA PET/CT as described previously .
Despite the consecutive inclusion of patients, the present population was biased because more than 20% of the patients were referred to 68Ga-PSMA-11 PET/CT due to equivocal findings in BS. The study was not a head-to-head comparative diagnostic test accuracy study. Therefore, no comparative analysis of diagnostic accuracy for the detection of bone metastases by BS was conducted. Likewise, the high proportion of patients with equivocal BS does not reflect the true frequency of equivocal findings in BS when SPECT/CT is applied, which in unselected populations has been shown to be approximately 10% at the time of initial staging . In the present setting, approximately 80% of the patients had a SPECT/CT performed as an add-on to the planar bone scintigraphy which is a limitation of the study. However, the use of SPECT/CT in patients with planar BS with possible benign or equivocal lesions reflects everyday clinical practice at our institution, where patients with a normal bone scintigraphy or harboring several obvious malignant lesions are not succumbed to additional SPECT/CT.