Prostate cancer accounts for 7.3% of new malignant tumors worldwide in 2020 and is one of the most common malignant tumors in middle-aged and elderly men, posing a serious threat to male life and health (1, 2). However, due to the incomplete popularization of tumor screening and insufficient attention to health checkups, the overall staging of prostate cancer patients in developing countries is later than that in developed countries, resulting in a poorer overall prognosis for patients. Compared with other organ tissues, prostate cancer cells have a greater affinity for bone tissue, with over 3/4 of prostate cancer patients will develop bone metastasis and about 50% of patients having bone metastasis at the initial diagnosis (3, 4). Currently, commonly used imaging methods for diagnosing prostate cancer bone metastasis include X-ray, CT, MRI, and ^99mTc-MDP whole-body bone imaging. Among them, ^99mTc-MDP whole-body bone imaging is widely used in clinical practice due to its low price and ability to image the entire body in a single examination, making it the preferred imaging method for screening prostate cancer bone metastasis (5). With the development of imaging technology and the advent of new specific imaging agents, molecular imaging techniques represented by PET/CT are playing an increasingly important role in the precise diagnosis and treatment of malignant tumors, with Prostate-specific membrane antigen (PSMA) as a targeted molecule receiving much attention in prostate cancer diagnosis and treatment (6). Compared with radiopharmaceuticals labeled with ⁶⁸Ga, the ¹⁸F-labeled PSMA imaging agent that has been clinically applied in recent years has the advantages of high synthesis rate, long half-life, and high image quality. Studies have shown that it has higher sensitivity and specificity in diagnosing prostate cancer lesions and is of significant value in initial diagnosis, staging, and therapeutic evaluation of prostate cancer (6–9). ¹⁸F-DCFPyL is a second-generation urea-based PSMA small-molecule inhibitor. Compared with the first-generation imaging agent ¹⁸F-DCFBC, its tumor affinity is nearly five times higher (9). At the same time, studies have shown that ¹⁸F-DCFPyL PET/CT imaging has a lower false positive rate in diagnosing bone metastasis in prostate cancer, especially in the ribs, scapula, and clavicle, compared with the more widely used ¹⁸F-PSMA-1007 in clinical practice (10). However, there are currently no studies comparing the diagnostic efficacy of ¹⁸F-DCFPyL PET/CT imaging and ^99mTc-MDP SPECT/CT bone imaging in prostate cancer bone metastasis. Based on this, this study retrospectively collected imaging and clinical data of prostate cancer patients who underwent both ¹⁸F-DCFPyL PET/CT and ^99mTc-MDP SPECT/CT bone imaging during the same period and further compared and analyzed the diagnostic efficacy of the two imaging methods in diagnosing prostate cancer bone metastasis, in order to provide assistance for early diagnosis and personalized treatment in clinical practice.

A total of 31 patients with prostate cancer, diagnosed based on pathology or BVC results, included 18 patients with bone metastasis. The patients had an average age of 67.83 ± 6.65 years (range: 54–78 years), and the time interval between the ¹⁸F-DCFPyL PET/CT and ^99mTc-MDP SPECT/CT imaging examinations was 10.6 ± 3.8 days (range: 1–26 days). Among the 18 patients, 5 had extensive bone metastasis, while the remaining 13 patients were diagnosed with a total of 84 bone metastatic lesions. The probabilities of bone metastasis occurring in the pelvis, spine, ribs, skull, and limbs were 72.2, 44.4, 38.9, 5.6, and 16.6%, respectively, with spine metastasis most commonly occurring in the lumbar vertebrae. The patients exhibited a mean serum t-PSA level of 70.88 ± 28.6 ng/mL, ranging from 0.15 to 372.08 ng/mL. Notably, 18 patients (58.1%) displayed a t-PSA level exceeding 20 ng/mL. In Table 1, the distribution of Gleason scores among the patients was as follows: 7 patients (22.6%) had a score of ≤6, 8 patients (25.8%) had a score of 7, and 18 patients (51.6%) had a score ≥ 8. According to the D’Amico risk stratification, 26 patients (83.9%) were classified as intermediate to high risk. High inter-observer agreement was observed for both patient-level and lesion-level analyses, with kappa values of 0.89 (95% CI 0.73–0.94) and 0.86 (95% CI 0.70–0.92) respectively.

Based on patient-level analysis, 19 patients were found to have bone metastasis based on ¹⁸F-DCFPyL PET/CT imaging. Of these, one patient exhibited notable ¹⁸F-DCFPyL uptake in the right sacroiliac joint, which was confirmed by biopsy as degenerative joint disease, while the remaining 18 patients who tested positive for ¹⁸F-DCFPyL PET/CT imaging were confirmed by pathology or BVC to have bone metastatic lesions. Based on lesion-level analysis, 83 lesions exhibited varying degrees of ¹⁸F-DCFPyL uptake on PET/CT imaging. One lesion was determined to be a false positive result (degenerative joint disease in the right sacroiliac joint) based on pathology or BVC results. Additionally, two false negative lesions were identified on ¹⁸F-DCFPyL PET/CT imaging. One lesion was located in the skull and demonstrated local increased bone density without an evident increase in radioactivity distribution. The other lesion was located in the lower segments of the left tibia, which was missed due to the limited imaging range of ¹⁸F-DCFPyL PET/CT (only covering the head to the thigh roots), and the patient lacked significant lower limb symptoms, so limb scanning was not performed.

Based on patient-level analysis, bone metastasis was diagnosed in 18 out of 32 patients using ^99mTc-MDP SPECT/CT imaging. Among them, four were later confirmed to be false positives, while the remaining 14 patients who tested positive for ^99mTc-MDP SPECT/CT imaging were confirmed by pathology or BVC to have bone metastatic lesions. Additionally, there were four cases where bone metastases were not detected by ^99mTc-MDP imaging, resulting in false negative results. At the lesion-level analysis, 67 lesions showed uptake of ^99mTc-MDP according to ^99mTc-MDP SPECT/CT imaging. Pathology or BVC confirmed that 61 of them were bone metastases from prostate cancer. The remaining 6 lesions, which included 3 cases of old rib fractures, 2 cases of degenerative changes in the lumbar vertebrae, and 1 case of osteoid osteoma in the proximal femur, were benign bone lesions and represented false positive results. Moreover, 23 bone metastatic lesions did not show obvious uptake of ^99mTc-MDP, which were false negative results.

The skeleton is the most common site of distant metastasis in prostate cancer, and bone-related events (SREs) caused by metastasis increase the risk of death in prostate cancer patients by 28% (13). In recent years, PSMA PET imaging technology has developed rapidly. Currently, the FDA has approved two PSMA-based PET/CT tracers, ⁶⁸Ga-PSMA-11 and ¹⁸F-DCFPyL, for clinical diagnosis of prostate cancer patients. Compared to ⁶⁸Ga-PSMA-11, ¹⁸F-DCFPyL has several advantages, such as higher drug yield, better image resolution, and easier commercial operation. Studies have shown that ¹⁸F-DCFPyL has higher SUV values and tumor-to-background ratios than ⁶⁸Ga-PSMA-11 in the diagnosis of prostate cancer primary lesions, especially for the diagnosis of smaller lesions (14). Therefore, ¹⁸F-DCFPyL has rapidly gained widespread popularity in routine clinical diagnosis of prostate cancer patients. However, there is still limited clinical data on the use of ¹⁸F-DCFPyL PET/CT imaging to diagnose bone metastasis. In a preliminary study of eight patients, Rowe et al. found that ¹⁸F-DCFPyL PET/CT imaging could detect occult bone metastases that conventional methods such as X-ray and CT cannot detect (15). In a prospective study of 130 patients with biochemical recurrence of prostate cancer in OSPREY, the diagnostic sensitivity and positive predictive value of ¹⁸F-DCFPyL PET/CT for bone metastases were 96.8 and 81.6%, respectively. However, this study did not further compare its diagnostic performance with traditional imaging methods (16).

The selected patients in this study were primarily categorized as intermediate to high risk based on their SPA levels and Gleason scores. A relatively high proportion of bone metastasis was observed, accounting for 58.06% (18/31) of cases, with the pelvis and lumbar vertebrae being the most frequently affected locations. This may be attributed to the abundance of red bone marrow in the pelvis and lumbar vertebrae, as well as the existence of the Batson venous plexus, which has rich blood flow and is more prone to bone metastasis. When analyzed on a patient basis, the sensitivity and specificity of ¹⁸F-DCFPyL PET/CT were 100.0 and 92.3%, respectively, while those of ^99mTc-MDP SPECT/CT were 77.8 and 69.2%. When analyzed on a lesion basis, the sensitivity and specificity of ¹⁸F-DCFPyL PET/CT were 97.6 and 95.7%, respectively, while those of ^99mTc-MDP SPECT/CT were 72.6 and 73.9%, respectively. The results of this study demonstrated that the diagnostic performance of ¹⁸F-DCFPyL PET/CT was similar to previous studies (17). However, the sensitivity and specificity of ^99mTc-MDP SPECT/CT bone scanning in this study were slightly lower than those reported in previous studies, possibly due to the fact that only SPECT/CT imaging was performed on the suspicious areas based on the whole-body planar imaging, and not whole-body computed tomography imaging on all patients (11). Among the 31 patients included in our study, 4 patients showed no obvious uptake of ^99mTc-MDP throughout the body, but were accurately diagnosed with bone metastasis using ¹⁸F-DCFPyL PET/CT, which allowed for more accurate tumor staging and effective optimization of treatment plans. Of the 84 confirmed metastatic lesions in this study, 23 lesions that were negative on ^99mTc-MDP SPECT/CT bone scanning were accurately identified by ¹⁸F-DCFPyL PET/CT imaging. These lesions did not show any significant changes in bone density or morphology on computed tomography scanning. This may be due to the fact that early bone metastases only cause changes in red bone marrow, and bone destruction and neogenesis are not yet significant. Due to the limitations of the principle of ^99mTc-MDP uptake, bone scanning cannot detect bone metastases at this stage, while ¹⁸F-DCFPyL, by specifically binding with PSMA on cancer cells, can detect these early metastatic lesions, which provides a significant advantage in their discovery (18).

In this study, two false negative lesions were detected by ¹⁸F-DCFPyL PET/CT imaging. One of them was found in a patient with castration-resistant prostate cancer (CRPC), where the lesion in the skull showed low uptake of ¹⁸F-DCFPyL, possibly due to low tumor cell activity or quantity after clinical treatment (19, 20). The other false negative lesion was located in the middle and lower part of the left tibia, which was mainly due to the limited routine imaging range of ¹⁸F-DCFPyL PET/CT. Both lesions showed obvious radiopharmaceutical concentration in the ^99mTc-MDP SPECT/CT bone imaging. Although these two patients were not affected in the final clinical staging and treatment plan due to the presence of other bone metastases, it suggests that a comprehensive diagnosis should be made by combining multiple imaging results, biochemical indicators, clinical history, and signs to avoid misdiagnosis or missed diagnosis of prostate cancer bone metastases. Furthermore, in this study, one false positive lesion was detected by ¹⁸F-DCFPyL PET/CT imaging, which was located in the right sacroiliac joint and was confirmed by pathological biopsy as degenerative joint disease. Although ¹⁸F-DCFPyL PET/CT imaging is a specific imaging method for targeting prostate cancer and its metastatic lesions, previous studies have shown that ¹⁸F-DCFPyL uptake can also occur to varying degrees in non-tumor lesion sites such as neovascularization, sympathetic ganglia, and bone degenerative lesions, which may be the main reason for false positive findings in such lesions (21).

This study has certain limitations. Firstly, it is a retrospective clinical study with fairly strict inclusion criteria, requiring patients to undergo both ¹⁸F-DCFPYL PET/CT imaging and ^99mTc-MDP SPECT/CT bone imaging within a short period of time (<30 days), and no changes in clinical treatment are allowed during the interval between the two examinations. This led to a relatively small number of patients included in this study, which may have resulted in certain biases in the research findings. Secondly, there is a lack of pathological gold standards for the diagnosis of bone metastases in this study, with most final judgments being made based on BVC results. Although all suspicious bone metastases were further evaluated by BVC, the presence of additional bone metastases cannot be completely ruled out.

In summary, our research demonstrates that ¹⁸F-DCFPyL PET/CT shows superior sensitivity, specificity, and accuracy in detecting bone metastases in patients with prostate cancer when compared to ^99mTc-MDP SPECT/CT bone scanning. While performing ¹⁸F-DCFPyL PET/CT for all prostate cancer patients may not be cost-effective, it remains a favorable option for patients at intermediate or high risk, even in cases where bone scanning and routine imaging yield negative results.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Ethic committee of China-Japan Union Hospital. The patients/participants provided their written informed consent to participate in this study.

BC and QW conceived and design the study, which were proofed by BC. XH, BJ, YC, and MZ collected and analyzed the data. XH wrote the manuscript. All authors contributed to the article and approved the submitted version.

This research was supported by Research Fund of Science and Technology Department of Jilin Province (No. 20210101445JC) and The Research Fund of Education Department of Jilin Province (No. JJKH20190080KJ).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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