Abstract
Background/Aim: This study aimed to evaluate the diagnostic accuracy of prostate-specific membrane antigen (PSMA)-directed positron emission tomography/computed tomography (PET/CT) in pelvic nodal staging, using postoperative histopathology data as the reference standard. Patients and Methods: From January 2020 to June 2024, 78 patients with clinically significant prostate cancer (PCa) (ISUP Grade Group 2) underwent radical prostatectomy plus extended pelvic lymph node dissection (ePLND): 60 (77%) vs. 18 (23%) men had an intermediate vs. high risk PCa. All the patients underwent PSMA PET/TC before surgery for clinical staging and nodes focal uptake (standardized uptake value “SUVmax) was evaluated to rule out the presence of metastases. Results: PSMA PET/CT was suspicious for nodes metastases in 16/78 (20.5%) men (median SUVmax 26.2), conversely, histology demonstrated nodes metastases in 18/78 (23.1%). PSMA PET/CT was negative for nodal involvement in all Grade Group 2 (GG2) PCa, positive in 4/4 (100%) GG3 PCa, and in 10/14 (71.4%) GG5 PCa. In detail, PSMA PET/CT was false negative in 2/4 PCa, characterized by GG5 plus ductal adenocarcinoma. Overall, PSMA PET/CT sensitivity, specificity, positive and negative predictive value, and diagnostic accuracy in diagnosing nodal metastases were equal to 87.5, 96.8, 87.5 96.7, and 92.3%, respectively. Conclusion: PSMA PET/CT demonstrated an overall diagnostic accuracy of 92.3% in nodal staging (100% in GG2 PCa), which decreased to 63.6% in GG5 PCa. In high-risk patients or in case of ductal adenocarcinoma, a negative PSMA PET/CT does not rule out the need for ePLND.
Prostate cancer (PCa) treatment has been improved following a multidisciplinary approach mandatory for locally advanced or oligometastatic disease. In this respect, an accurate clinical staging is essential for planning a tailored therapy for each patient. Radical prostatectomy (RP) with or without lymphadenectomy and/or definitive radiotherapy (RT) are the main curative treatments for PCa (1). However, a significant proportion of patients may experience disease recurrence following these interventions. Therefore, a more accurate disease staging could prove beneficial in enhancing initial treatment, subsequently reducing the risk of relapse (2). The international guidelines strongly recommend to perform computed tomography (CT) combined with bone scan in men with intermediate to high-risk PCa; in this context, the novel radiopharmaceuticals for molecular imaging that target the prostate-specific membrane antigen (PSMA) have gained traction (3). PSMA is highly expressed in most primary and metastatic PCas and PSMA inhibitors conjugated with the radionuclides 68Ga-Gallium and 18F-fluoride have been well-explored and successfully translated for the clinical diagnosis of PCa (4-11). In fact, PSMA positron emission tomography/computed tomography (PET/CT) has become an established imaging modality for restaging patients with early biochemical recurrence to perform, in selected cases, PSMA guided salvage radiotherapy (12). More recently, literature studies have demonstrated the higher accuracy (32%) of molecular imaging with PSMA PET/CT compared to conventional imaging also in the setting of primary diagnosis and staging of high-risk PCa (13). Accordingly, the European Association Urological guidelines recommend performing PSMA-PET/CT imaging in the primary staging of intermediate and high-risk PCa patients (3). However, in the absence of clear data regarding the ideal management and prognosis of patients staged with PSMA-PET/CT, they advise caution when basing therapeutic decisions on molecular imaging findings, especially in case of patients with metastases detectable only by PSMA PET/CT. Therefore, more studies evaluating the diagnostic performance of PSMA-PET/CT and its impact on patient management are needed.
This prospective study, evaluated the diagnostic accuracy of PSMA PET/CT in pelvic nodal staging using postoperative histopathology data as the reference standard.
Patients and Methods
From January 2020 to June 2024, 78 patients (median age: 63 years; range=46-75 years) with biopsy proven (14, 15) clinically significant PCa (ISUP Grade Goup 2/Gleason score 3+4) (16, 17) underwent RP: median PSA was 12.5 ng/ml (0.3-100 ng/ml) and digital rectal examination was suspicious in 20/78 (25.6%) men; 60 (77%) vs. 18 (23%) men had an intermediate vs. high risk PCa. All the patients underwent PSMA PET/TC (Figure 1) before surgery (70 laparoscopic vs. 8 open approach) combined with extended pelvic lymph node dissection (ePLND: external, ipogastric and common iliac nodes, obturator nodes). PET/CT imaging was performed using a CT-integrated PET scanner Biograph 6 (Siemens, Knoxville, TN, USA) 60-90 min after the intravenous injection of 74-185 mBq mCi of Gallium 68 (68Ga) and Fluoride 18 (18F), which was prepared with a fully automated radiopharmaceutical synthesis device; the raw images were processed with appropriate iterative reconstruction techniques to obtain PET, CT, and PET-CT fusion sections in the axial, coronal, and sagittal planes with a thickness of approximately 0.5 cm by two experienced nuclear medicine specialists, who were blinded to the clinical data. Only patients with ductal adenocarcinoma combined with GG5 PCa underwent, lung and abdominal CT plus bone scan. PSMA PET/CT was performed for clinical staging; in detail, PSMA focal uptake and avidity (standardized uptake value “SUVmax) evaluation was considered suspicious for metastases (8, 18).
Results
No patients had visceral metastases. Six patients (7.7%) had bone lesions (fewer than three lesions), while 16 out of 78 (20.5%) had nodal findings suspicious for metastases, with a median SUVmax of 26.2 (range=6.5-78), respectively. All patients underwent multidisciplinary evaluation before RP. The 18 men with high-risk PCa and imaging suspicious for bone and/or nodal metastases were advised that surgery was the first step in a multimodal approach that would require further therapies. After institutional review board and ethical committee approval were granted, the informed consent was obtained from all individual participants included in the study. Post-operative complications were 5/78 (6.4%) symptomatic lymphoceles and 1/78 (1.2%) urinary leakage that needed a prolonged time of hospitalization. The definitive specimen showed a pT2 vs. pT3a vs. pT3b PCa in 54/78 (69.2%) vs. 4/78 (5.2%) vs. pT3b 20/78 (25.6%) cases; a median of 13 (range=6-23) nodes was removed. 34/78 (43.6%) had GG2 PCa, 20/78 (25.6%) had a GG3 PCa, and 24/78 (30.8%) had a GG5 PCa. Moreover, 26/78 (33.3%) had positive surgical margins. PSMA PET/CT was positive for nodal metastases in 16/78 (20.5%) men. In contrast, histology demonstrated nodal metastases in 18/78 (23.1%) (Table I). Clinical parameters, definitive histology, and PSMA findings of men with nodal metastases are listed in Table I. Overall, PSMA PET/CT identified nodal metastases in 14/18 (77.8%) men with histologically proven metastases. In only two cases, suspicious nodes were located outside the conventional ePLND sites (pararectal and anterior to the bladder) rather than in the standard locations, such as the obturator, external iliac, hypogastric, and common iliac nodes. PSMA PET/CT was negative for nodal involvement in all GG2 PCa, positive in 4/4 (100%) GG3 PCa, and in 10/14 (71.4%) GG5 PCa. In detail, PSMA PET/CT resulted false negative in 2/4 PCas characterized by GG5 plus ductal adenocarcinoma.
Overall, PSMA PET/CT sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) and diagnostic accuracy in diagnosing nodal metastases were equal to 87.5, 96.8, 87.5, 96.7, and 92.3%, respectively. Specifically, diagnostic accuracy in diagnosing nodal metastases in GG3 vs. GG5 PCas was equal to 66.7 vs. 63.6%, respectively.
Discussion
Although CT and bone scan are recommended for clinical staging and multiparametric magnetic resonance imaging (mpMRI) has demonstrated high accuracy in the diagnosis (19, 20) and local staging (21) of PCa, multiple studies have confirmed the higher diagnostic accuracy of molecular imaging in high-risk PCa staging (22). In recent years, the staging and therapeutic role of ePNLD has been evaluated. While men with limited nodal disease (≤2 positive nodes) demonstrated favorable cancer-specific survival (about 95% at five years after surgery) (23), the introduction of new and effective systemic therapeutic agents in clinical practice could limit ePNLD to selected cases, thereby reducing the clinical complications associated with the procedure. In this respect, the use of PSMA PET/CT, compared to CT and bone scans, improves clinical staging and allows for a change in management in 21% to 28% of cases (24, 25). Chow et al. (26), in a study of 687 patients, showed a significantly higher sensitivity (73.2 vs. 38.5%) and specificity (97.8 vs. 83.6%) of PSMA PET/CT compared to CT in nodal staging. Pienta et al. (27), in a study of 252 high-risk PCa patients, showed that 18F-PSMA PET/CT had a higher PPV (86.7% vs. 28.3%), and specificity (97.9% vs. 65.1%), and a slightly higher NPV (83.2% vs. 77.8%) compared to CT. Pepe et al. (28) reported that 68Ga-PSMA PET/CT was more accurate than CT and bone scan in the staging of high-risk PCa, leading to a change in the therapeutic strategy in 10% of the cases. Hope et al. (29), in a study of 764 patients, demonstrated that PSMA PET/CT had a sensitivity and specificity of 40% and 95%, respectively, for detecting pelvic lymph nodes when compared with histopathology on a per-patient basis using nodal region correlation. Rajwa et al. (30), in a study involving 165 high-risk patients submitted to RP and PNLD, showed a 83% diagnostic accuracy of PSMA PET/CT in diagnosing nodal metastases. Moreover, Esen et al. (31), in a study of 96 men submitted to RP and ePNLD, reported the following performance metrics for 68Ga-PSMA PET/CT: sensitivity of 53.3%, specificity of 98.8%, PPV of 88.9%, NPV of 92.0%, and accuracy of 91.7%. Stabile et al. (32) reported that the high NPV in men with a lower risk of lymph node invasion might be clinically useful for reducing the number of unnecessary PLND. Conversely, in high-risk patients, a negative PSMA PET/CT does not eliminate the need for ePLND.
In our series, PSMA PET/CT found nodal metastases in 14/18 (77.8%) men with histologically proven metastases. PSMA PET/CT was negative for nodal involvement in all GG2 PCa, positive in 4/4 (100%) GG3 PCa, and in 10/14 (71.4%) GG5 PCa. In detail, PSMA PET/CT resulted in false negatives in 2/4 cases of GG5 PCa combined with ductal carcinoma.
Study limitations. First, the results only refer to the correspondence of nodes between PSMA PET/CT and the definitive specimen. Second, data on oncological outcomes of RP plus ePLND (postoperative PSA value and PSMA PET/CT evaluation) were not reported because some patients, underwent multimodal therapy as planned. Third, none of the high-risk or metastatic patients underwent a control arm to evaluate oncological outcomes with RT combined with androgen deprivation therapy. Finally, in the presence of ductal adenocarcinoma, additional imaging with CT, bone scans, or FDG PET/CT should be considered alongside PSMA PET/CT to reduce false negative results (33, 34).
In summary, PSMA PET/CT can help identify suspicious nodes outside conventional sites of ePLND or guide stereotactic salvage radiotherapy in cases of PSA or clinical relapse. Additionally, the high NPV of PSMA PET/CT in intermediate-risk PCa could be useful in avoiding unnecessary ePLND.
Conclusion
PSMA PET/CT demonstrated an overall NPV and diagnostic accuracy of 96.7 and 93.2%, respectively, in nodal staging of csPCa. However, diagnostic accuracy in GG5 PCa decreased to 63.6%. Therefore, in high-risk PCa or cases of ductal adenocarcinoma, a negative PSMA PET/CT does not eliminate the need for ePLND.
Acknowledgements
The Authors thank the Nuclear Medicine Unit of Cannizzaro Hospital (Catania, Italy) for the images.
Footnotes
Authors’ Contributions
Conceptualization: P.P., P.L.; Methodology; P.P., P.L., F-V-; Software: P.L., F.V.; Validation: P.P., P.L.; Formal Analysis: P.P, P.L., F.V.; Investigation: P.P.,P.L.; Resources: P.P.,P.L.; Data Curation: P.P., P.L.; Writing – Original Draft Preparation: P.P., P.L., F.V.; Writing – Review & Editing: P.P., P.L., F.F.; Visualization: P.P, P.L., C.M., F.V., P.M., F.F.; Supervision: P.P., P.L.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
- Received September 1, 2024.
- Revision received September 14, 2024.
- Accepted September 16, 2024.
- Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).