Malignant skeletal involvement of PCa develops as a multistep process initiating as intramedullary lesions in the distribution of the red active marrow . In the marrow, tumor cells follow a lag phase of undetermined duration comprising a dormant phase followed by a more aggressive active phase with tumor-associated osteolysis and tumor-induced bone formation that dictates the final appearance of the lesion as OB or OL. Thus, metastatic processes are present in the bone marrow long before they give rise to derangement of the normal bone tissue architecture .
The incidence of bone metastases at staging of patients with newly diagnosed high risk PCa varies between 6.6–36.1% in different publications depending on the size of cohort and either SPECT or PET technology was used [4, 27–32]. Clinical guidelines [6–9], recommend performance of BS at staging when PSA is ≥20, clinical stage is T2 and PSA is ≥10 ng/dL, clinical stage is T3 or T4, Gleason score is ≥8, or any symptoms are suggestive of bone metastases. In the current study, we found metastatic involvement in 19.5% of patients with newly-diagnosed prostate cancer. As expected, patients with skeletal metastatic involvement were those with higher risk based on ISUP score and PSA levels. It should be noted however that metastatic skeletal spread was found also in 1.5% of patients with low risk (GG 1) and 4.6% of patients with intermediate risk (GG 2/3) (a total of 10.7% of patients with Gleason Score ≤7) and in 10.7% of patients with PSA ≤10 ng/dL.
Metastatic skeletal spread was found in almost 9% of high-risk patients with GG 4 or 5, in 27% of patients with PSA >10 ng/dL (include as high as 39% of patients with PSA level of 20 ng/dL and higher).
In the clinical setting, the extent of skeletal involvement influences the choice of the treatment. Patients with 5 or fewer metastatic bone lesions were reported to have a longer overall survival than patients with more than 5 metastases (73% vs 45% at 5 years and 36% vs 18% at 10 years), as well as longer disease-free survival. A specific cohort of patients with "oligometastases" is now recognized at staging evaluation [22, 33]. Treatment options for oligometastatic and extensive disease vary greatly . In the current study, while a total of 19.5% of the study cohort were found to have malignant skeletal involvement, only 7.6% had extensive disease and the others had a single lesion or oligometastatic disease.
Bone metastases of PCa are considered OB based on their appearance on conventional radiographs. However, studies have shown a high heterogeneity of lesions, with synchronous osteolysis, even when the blastic appearance predominates. Histomorphometric studies have shown that OB lesions are mixed in nature with increased activity of both osteoblasts and osteoclasts contributing to the histological frailty observed in the skeleton in PCa patients, even in the presence of dense metastatic lesions .
Among patients with bone metastases we found OB type metastases in 70.7%. In only slightly more than half of them (54.1%) OB type spread was "pure" while in other 45.9% OL and/or IM metastases were also present. Patients with extensive disease, with GG 4/5 and with high PSA levels, had more often combined IM+cortical metastases, probably reflecting the aggressiveness of the disease, when mature metastases cortical ones and new marrow deposits co-exist.
In almost one third of patients with bone metastases, only OL type and/or IM metastases were present. We did not perform a head-to head comparison between the PET findings and bone scintigraphy, but these results raise a question regarding the ability to relay on BS for staging of newly diagnosed prostate cancer and for assessment of disease extent in view of the limited sensitivity of BS in detection of lytic type and marrow-based metastases.
Two recent manuscripts, one evaluating 30 patients and the other evaluating 35 PCa patients, reported a high sensitivity of PSMA PET/CT in detection of the various types of bone metastases [18, 29]. In 2015, Ceci, et al  published a study on the incidence of various metastases type in 140 newly diagnosed prostate cancer patients with bone involvement as identified on C-11 Choline PET/CT. There are some differences in the findings presented by the above publication and ours probably. We found a higher incidence of IM metastases (21.8% of the patients with metastatic spread), compared to 6.5% in the C-11 Choline PET/CT report. We found "pure" OB type metastases in 38.3% of the patients and "pure" OL type metastases in 4.3% compared to 62.3% and 26.1% respectively, on the C-11 Choline PET/CT study. Possible causes for the differences may be the different performance of labeled choline and labeled PSMA, difference in cohort size, and the fact that our cohort is composed of consecutive patients. The national-reimbursement of PSMA PET/CT in newly diagnosed patients with intermediate and high risk prostate cancer, decreases the potential bias in referral of patients for PET/CT staging.
As previously described by others, increased uptake of labeled PSMA in the skeleton may be seen also in non-malignant lesions [21, 23, 35]. A list of benign bone lesions were reported to be associated with labeled PSMA accumulation including fibrous dysplasia, Paget’s disease, enchondroma, fracture. These lesions can be accurately diagnosed on the data of contemporaneous CT and should not be reported as metastases. Increased uptake in the rib with no morphological abnormality or other skeletal lesions is a common finding that is likely to be a false positive site of uptake and should be mentioned with caution. Only two lesions reported as equivocal were found in the current study to be metastases.
PSMA PET/CT staging of 963 consecutive patients with newly diagnosed intermediate and high-risk PCa revealed malignant skeletal involvement in 19.5% of the patients but only 7.6% had extensive disease while the others had a solitary lesion or oligometastatic disease. Extensive disease was closely related with high ISUP Grade and high PSA level but was found also in patients with lower ISUP Grade and/or PSA level. Although bone metastases of PCa are considered OB, OL type and IM metastases are commonly identified on PET/CT.