This retrospective analysis of
68Ga-PSMA PET/CT scans in 234 patients with advanced prostate cancer revealed a predominance of lymph node metastases in 46.1% (pelvic in 41% and abdominal in 30.3%) and bone metastases in 61.9% (bone carcinomatosis in 30.6% and oligometastatic in 8.9%). Level 1-4 lymph node positivity was evident in the presence of lung and liver metastasis or seminal vesicle invasion, whereas the presence of bone metastasis was associated with level 1-2 lymph node positivity. Bone metastasis was evident in all patients with liver and lung metastasis, while present at oligometastatic stage only in patients with seminal vesicle invasion.
In the current cohort: lymph node metastases in 46.1% of patients and bone metastases in 61.9%, as well as pulmonary (7.6%), hepatic (7.2%), adrenal (2.5%), peritoneal and (0.8%), pleural (2.9%) metastases in a previous retrospective analysis of 240 patients with prostate cancer, 68Ga PSMA I&T PET/CT revealed lymph node metastases in 62.5% of patients and bone metastases in 33.7%, together with local recurrences (26.6%) as well as pulmonary (4%), hepatic (2%), adrenal (1%), peritoneal (0.5%), muscular (0.5%) and testicular (0.5%) metastases 19. In another retrospective analysis of 101 patients with increased PSA levels after radical prostatectomy, the 68Ga-PSMA-I&T PET/CT revealed lymph node metastases in 73.3% of patients and bone metastases in 30.7%, together with local recurrences (16.8%) and other metastases (5.9%) 20. In a retrospective analysis of 83 consecutive patients (PSA: 0.81, range: 0.01 - 128 ng/mL) with biochemical relapse after prostatectomy, the 68Ga PSMA I&T PET/CT revealed local recurrent cancer in 22% of the patients, lymph node metastases in 35% and distant metastases in 18% 17.
In a retrospective analysis of the diagnostic value of 68Ga-PSMA PET/CT in 901 representative tumor lesions of 319 patients, 13 lesions were defined as local relapses after prostatectomy, while 328 were reported as lymph node metastases, 359 as bone metastases, 129 as soft tissue metastases and 72 as vital tumor lesions within the prostate gland 21.
In our patient group, median SUVmax in lymph nodes ranged from 8.7 in supraclavicular and/or neck lymph nodes to 11.9 in abdominal lymph nodes, while the size of lymph nodes detected via 68Ga-PSMA PET/CT ranged from 13.9 (range: 5-29) mm (neck lymph nodes) to 19.3 (range: 6-29) mm (abdominal lymph nodes). Similarly, in a retrospective analysis of 90 patients with prostate cancer referred for 68Ga-PSMA PET/CT, lymph node metastasis was reported in 26.7% of patients together with median nodal diameter of 10.9 mm (range: 3.9–32.9) and SUVmax of 10.6 12.
In a previous study of 25 patients with biochemical recurrence after radical prostatectomy, 68Ga-PSMA-I&T PET/CT revealed presence of lymph node metas-tases in 60.5% of patients and with SUVmax of 21.9 (ranged 4.2–89.0) 22.
The range (5-54 mm) for the size of lymph nodes de-tectable via 68Ga-PSMA-I&T PET/CT in the current study seems notable given the significant difference reported in median size of lymph node metastases detected vs. undetected (13.6 versus 4.3 mm) via 68Ga-PSMA PET/CT and the potential influence of lymph node metastasis size on the diagnostic accuracy of 68Ga-PSMA PET/CT 23.
The sensitivity and specificity of 68Ga-PSMA PET/CT in the detection of lymph node metastasis has been reported to range from 61.1-80.0% and 90.0-100.0%, respectively in past studies 6,12,21.
In accordance with consideration of bone as the most frequent site of metastatic spread in prostate cancer 24 bone metastases were detected in 61.9 % of patients and with median SUVmax of 11.9 in our cohort. Compared to the current study findings of the diagnostic accuracy of 68Ga-PSMA PET/CT in detecting bone metastasis, lower detection rates (12.2%) with similar SUV (SUVmax: 11.6) 12 as well as lower detection rates (34.2-36%) 22,25 with higher SUV (SUVmax: 27.1) 22 or lower PSA levels (median 1.99 ng/ml, ranged 0.2-59.4) 25 have been reported among recurrent prostate cancer patients in past studies.
In a retrospective study of 155 consecutive patients with recurrent disease, the overall rate of bone metastases was reported as 32%, which ranged from 15% in patients with PSA <1 ng/ml to 39% in those with PSA ≥2 ng/ml 26.
Accordingly, in a systematic review of 37 studies on the utility of 68Ga-PSMA PET/CT for the detection of bone metastases, the prevalence of pathological bone lesions was reported ranging from 5% to 60% 24. The authors concluded that the diagnostic performance of 68Ga-PSMA PET/CT was higher with increased PSA levels and it was superior to bone scintigraphy in the detection of bone lesions in terms of sensitivity (99% vs 73%) and specificity (100% vs. 98%), whereas its diagnostic performance in progressive metastatic disease was considered as questionable 24.
The lung was the second most common distant organ metastasis (7.6%) in our study and lung metastasis was associated with the lowest SUVmax scores (median 4.3) amongst other metastases. The lung has been considered as the second organ involved after bone in patients with prostate cancer, while the lack of any significant difference in SUVmax values between lung cancer and histologically proven prostate cancer has also been emphasized due to PSMA expression in tumor associated neovasculature in patients with primary lung cancer 27,28. In fact, 68Ga-PSMA PET/CT is considered less valuable in the lungs, since it fails to discriminate reliably between pulmonary metastases and primary lung cancer in prostate cancer patients 7,28.
Gleason scores of > 7 or PSA levels ≥ 10 ng/ml have been associated with significantly higher uptake of 68Ga-PSMA in patients with prostate cancers 29, while the increasing rate of bone metastases has been reported with higher PSA levels or the PSA doubling time 24,26. This seems notable given the median Gleason score of 8 6-10 and median PSA level of 21.7 ng/mL (0.2-880) in the current study. Nonetheless, it has been emphasized that a continuous increase in PSA level does not automatically correlate with an increase in tumor detection 21 and a high PSA-value may also predict lower diagnostic performance of 68Ga-PSMA PET/CT for detection of affected regions due to a higher likelihood of microscopic spread 30.
Given the earlier occurrence of increased PSMA ex-pression than the expected morphological alterations in bone metastases 31 and the superiority of 68Ga-PSMA-ligand imaging to morphological imaging in the detection of lymph node metastases 7,32 the current study findings emphasize the role of 68Ga-PSMA PET/CT in timely and accurate diagnosis of lymph node and bone involvement in patients with PSA persistence or progressive metastatic disease 19,24. This seems critical in the management of prostate cancer in terms of potential for allowing planning of a more tailored therapeutic strategy and use of salvage procedures (e.g. secondary lymphadenectomy, targeted radiation therapy) with a potentially curative intent 7,31,33,34. However, in unclear 68Ga-PSMA PET positive lesions, further diagnostic work-up with morphological correlation and confirmation via other imaging techniques such as MRI, ultrasound or biopsy are considered necessary 7.
The current study findings also revealed data on the concomitant presence of lymph node and distant organ metastases. Level 1-4 lymph node positivity was evident in the presence of lung and liver metastasis or seminal vesicle invasion, whereas the presence of bone metastasis was associated with level 1-2 lymph node positivity. Although only 8.9% of bone metastases were at the oligometastatic stage compared with the detection of multi-metastatic bone metastases in 22.2% of patients in this cohort, it should be noted that bone metastasis was evident in all patients with liver and lung metastasis, while it was at the oligometastatic stage only in patients with seminal vesicle invasion.
This finding revealed an absence of concomitant lung or liver metastases and level 3-4 lymph node metastases, but positivity of seminal vesicle invasion in patients with oligometastatic stage bone metastasis. This seems notable given that prompt detection of prostate cancer recurrence is considered of critical importance since metastases are more likely to be locally confined or oligometastatic at this point enabling the use of metastasis-directed therapies, both lymphadenectomy and radiotherapy 6.
This study has some limitations: The first is retrospec-tive, single centered, study in a certain date range. A second limitation is the lack of histological validation for positive findings on 68Ga-PSMA PET/CT. Despite these limitations, this study will provide valuable literary contributions to metastases in prostate cancer patients.
In conclusion, the findings of this retrospective cohort of patients with advanced prostate cancer showed the value of 68Ga-PSMA PET/CT in detecting coexistence rates of metastases in advanced prostate cancer.
Acknowledgements
The research was not financially supported by grants or any other kind of funding from any pharmaceutical company or other possible sources. All the authors had an active involvement in data collection and analysis, as well as writing, preparing and reviewing the manuscript.
Author contributions: All authors designed the study, analyzed the data and contributed to the writing of the paper. All authors statistically analyzed the data. All authors contributed to the writing of the paper. All the authors accept responsibility for the data and the accuracy of the data analysis.
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Conflicts of interest: The authors have no conflict of interests to declare.
Financial Disclosure: The authors declared that this study has received no financial support.