Abstract
Background/Aims
Current guidelines suggest that the indications for pelvic lymph node (LN) dissection (PLND) during radical prostatectomy (RP) should rely on nomograms predicting their involvement. Positron emission tomography/computed tomography (PET/CT) with prostate-specific membrane antigen (PSMA) radioligand is gaining acceptance as routine diagnostic test before RP in patients with intermediate/high-risk prostate cancer (PC). In this study, we examined the effect of preoperative PET/CT on the accuracy of the nomograms.
Materials and methods
Patients with intermediate/high risk PC showing no extraprostatic disease on PET/CT-PSMA underwent RP with PLND and were followed postoperatively for at least 6 months. Patients with detectable (>0.1 ng/mL) postoperative prostate-specific antigen levels underwent re-evaluation with PET/CT-PSMA.
Results
A total of 70 patients underwent RP for intermediate (34 patients) or high-risk disease (36 patients). According to the Partin, MSKCC, and Briganti 2012 nomograms, positive LNs were expected in 7, 13, and 12 patients, respectively. At PLND, 1 positive LN was found in a single patient (p < 0.05 compared with the expected number of patients from all nomograms). Postoperatively, 10 patients developed detectable prostate-specific antigen levels. One patient exhibited radioligand uptake that could indicate LN involvement. Considering these 2 patients as failures, the negative predictive value of PSMA-PET/CT for LN involvement was 97.1%.
Conclusions
Preoperative PSMA-PET/CT with no extraprostatic uptake before RP in patients with intermediate to high-grade PC is highly accurate for ruling out LN involvement, superior to the routinely used nomograms. Its use induced stage migration, rendering predictive nomograms irrelevant.
Keywords: Pelvic lymph node dissection, Radical prostatectomy, Nomograms, Prostate-specific membrane antigen, Positron emission tomography/computed tomography
1. Introduction
Pelvic lymph node dissection (PLND) is considered the most accurate method for detecting lymph node (LN) invasion in prostate cancer (PC). It also provides accurate staging information and is useful for planning adjuvant therapies.[1] Despite thorough investigation, PLND was not shown to improve the oncological outcome, including biochemical recurrence, metastasis-free, cancer-specific, or overall survival rates.[2]
Pelvic lymph node dissection is not an innocent procedure. It adds 23–51 minutes to surgery time during standard PLND (sPLND) and 30–72 minutes in extended PLND (ePLND).[3] Though rare, PLND might be associated with significant intraoperative complications, including major vascular injury, ureteral injury, and obturator nerve injury. Postoperative complications include symptomatic lymphocele, lymphedema, ileus, deep vein thrombosis, and pulmonary embolism. The reported rate of Clavien-Dindo grade 3–4 complications attributed to PLND ranges from 0% to 5%.[3] The association between PLND and continence recovery is not clear but Sagalovich et al. observed a worse potency outcome when >20 LNs were retrieved and Van der Poel et al. observed the same when >10 were retrieved.[4,5]
The reported frequencies of LN involvement in modern series range from 11.1% in patients at low risk to 15.2% in the intermediate category and 20% in the high-risk group.[6] Subjecting only patients with a high risk of LN involvement to PLND is logical, and several nomograms were developed for this purpose. The commonly used ones include the Partin, MSKCC, and Briganti 2012 nomograms,[7,8] all of which have high accuracy. External validation of the nomograms using a population of 12,009 patients, including 1158 patients (9.6%) with involved LNs, showed area under the curve of 0.79, 0.83, and 0.83, for the Partin, MSKCC, and the Briganti 2012 nomograms, respectively.[9] The American Urological Association and National Comprehensive Cancer Network guidelines recommend performing PLND when the risk of positive LNs according to nomograms is more than 2% and European Urologic Association when more than 5%.[1,10,11]
In recent years, prostate-specific membrane antigen (PSMA)-targeting radioligands, including 68Ga-PSMA-11 and 18F-PSMA-1007, were developed for pretreatment and posttreatment evaluation of PC patients.[12] The negative predictive values (NPV) for predicting LN involvement of 68Ga-PSMA-11 were studied in a mixture of patient populations and were found to be 81%–92.3%.[12–15] Stabile et al. performed a meta-analysis of 27 studies, including 2823 patients, using 68Ga-PSMA-11, 18F DCFPyL, 18F-rhPSMA-7, 18F-PSMA-1007, and 64Cu-PSMA, and found an NPV of 81%.[16] These studies concluded that positron emission tomography/computed tomography (PET-CT) is still not a good replacement for PLND, especially in high-risk patients. The drawback of these studies is the use of various radioligands and mixed populations of patients, including candidates for surgery and radiotherapy as well as patients who underwent surgery despite evidence of radioligand uptake in LNs. Better results were found in a more uniform population of candidates for radical prostatectomy (RP).[17] In this study, magnetic resonance imaging and 68Ga-PSMA-11 showed a similar NPV (87% and 89%) and combining the 2 modalities did not increase the NPV (90%).
In the current study, we examined the NPV of PSMA-PET/CT in patients with PC who were candidates for RP with no evidence of extraprostatic involvement. The observed pathological findings were compared with the findings predicted by the nomograms.
2. Materials and methods
2.1. Patients
Prostate cancer was diagnosed by transrectal or transperineal biopsies. A 12-core template was acquired in 40 patients and additional imaging-guided biopsies in 30 patients. Patient risk groups were determined according to the American Urological Association Risk Group Classification for Clinically Localized Prostate Cancer[1]; the study included patients with intermediate- or high-risk PC. The risk of LN involvement was determined by the Partin, MMSK, and Briganti 2012 nomograms.[8,9] All patients underwent preoperative imaging with either 68Ga-PSMA-11 or 118F-PSMA-1007 PET/CT no more than 3 months before surgery showing no extraprostatic disease. None of the patients received prior treatment for PC. The study was conducted in accordance with the Declaration of Helsinki. Because this was a retrospective study based on medical chart review and standard follow-up data, informed consent was waived by the Hadassah Medical Organization (HMO) IRB (# 0155-23).
2.2. Imaging
Positron emission tomography/computed tomography scans were performed using the following protocol: A low-dose CT was acquired before each PET study for attenuation correction (Smart current: 15–20 mA, noise index: 14.52), followed by a second diagnostic CT with or without intravenous contrast (smart current: 100–500 mA, noise index: 15.32). The PET study was acquired 60 ± 8 minutes after the injection of either 18F-PSMA-1007 (3.4 ± 0.3 MBq/kg) or 68Ga-PSMA-11 (2 ± 0.4 MBq/kg). All patients received an iodine-based oral contrast during the uptake period and, when possible, an intravenous contrast (Omnipaque 350, GE Healthcare, 1 mL/kg) before the diagnostic CT. The images were interpreted by 2 nuclear medicine experts with more than 20 years of experience (MO and SBH).
2.3. Surgery and postoperative follow-up
All surgeries were performed using the Da Vinci Si system by 2 experts in urology (ONG and VY). Standard pelvic lymph node dissection, including the external iliac and obturator LNs, was performed in all patients. Final pathology was compared with the nomogram-predicted pathology using Fisher’s exact test. Postoperative follow-up included prostate-specific antigen (PSA) testing at 6 weeks and 3, 6, 12, 24, and 30 months after surgery. Any PSA rise above 0.1 ng/mL triggered reevaluation with PSMA-PET/CT. Patients were treated based on PET/CT findings and PSA dynamics.
3. Results
A total of 70 patients (mean age, 65.7 years; SD, 5.3 years) were included in the study. Their average preoperative PSA level was 12.1 ng/mL (SD, 9.4 ng/mL; range, 0.15–51 ng/mL). Their International Society of Urological Pathology (ISUP) grades and clinical stages are shown in Table 1. All patients underwent preoperative evaluation using either PET/CT 68Ga-PSMA-11 (13 patients) or 18F-PSMA-1007 (57 patients) with no evidence of extraprostatic disease.
Table 1.
Preoperative and postoperative characteristics of the patients.
| Characteristics | Preoperative, n (%) | Postoperative, n (%) |
|---|---|---|
| Stage | Clinical stage | Pathological stage |
| T1c | 37 (52.8) | |
| T2a | 7 (10) | |
| T2b | 15 (21.4) | |
| T2c | 7 (10) | 32 (45.7) |
| T3a | 4 (5.7) | 27 (38.6) |
| T3b | 11 (15.7) | |
| PSA, ng/mL | ||
| 0–4 | 4 (5.7) | |
| 4.1–10 | 38 (54.3) | |
| 10.1–20 | 18 (25.7) | |
| >20 | 10 (14.3) | |
| ISUP grade group | ||
| 1 | 3 (4.3) | |
| 2 | 19 (27.1) | 21 (30) |
| 3 | 25 (35.7) | 36 (51.4) |
| 4 | 10 (14.3) | 6 (8.6) |
| 5 | 13 (18.6) | 7 (10) |
ISUP = International Society of Urological Pathology; PSA = prostate-specific antigen.
According to their preoperative parameters, 34 patients had intermediate-risk disease and 36 had high-risk disease. The Partin, MSKCC, and Briganti 2012 nomograms predicted positive LNs in 7.3 (SD, 6.8), 13.1 (SD, 11.6), and 11.7 (SD, 12) patients, respectively. All patients underwent robotic-assisted RP with sPLND. The median LN count was 9 (interquartile range, 6–15). Negative surgical margins were found in 58 (82.9%) patients and positive margins in 12 (17.1%). Final pathology showed a single positive LN (a single focus with a diameter of 1 mm) in 1 patient (Fig. 1), a 66-year-old with a preoperative PSA level of 11.4 ng/mL, ISUP 2 in 50% of the biopsy cores, and clinical stage T2b. His risks of positive LNs were 18%, 16%, and 10% according to the Partin, MSKCC, and Briganti 2012 nomograms, respectively. The difference between the observed (1 patient) and expected number of patients with positive LN was statistically significant (p = 0.03, 0.0005, and 0.001 for the Partin, MSKCC, and Briganti 2012, respectively).
Figure 1.
Photomicrograph of a lymph node from PLND of a 66-year-old with a preoperative PSA level of 11.4 ng/mL, ISUP 2 in 50% of the biopsy cores, and clinical stage T2b. The risks of positive LNs in this patient were 18%, 16%, and 10% according to the Partin, MSKCC, and Briganti 2012 nomograms, respectively. A microscopic metastasis (arrow) can be seen. The metastasis was missed by the 18F-PSMA-1007 PET/CT (hematoxylin and eosin, ×10). ISUP = International Society of Urological Pathology; LN = lymph node; PET/CT = positron emission tomography/computed tomography; PLND = pelvic lymph node dissection; PSA = prostatespecific antigen; PSMA = prostate-specific membrane antigen.
After a median follow-up of 16 months (interquartile range, 7–22.75), 10 patients developed detectable PSA levels. All were re-evaluated with 18F-PSMA-1007 PET/CT. In 1 patient, a 58-year-old man with preoperative PSA of 11 ng/mL, ISUP 3, and clinical stage T2b, PET/CT suggested involvement of a 4-mm LN in the left pelvic side wall (Fig. 2). Radioligand uptake was also noted in a clavicle bone, iliac bone, presacral node, and para-aortic node, each in a single patient. In the other 5 patients, PET/CT did not reveal any suspicious uptake. Considering the patient who had a negative preoperative study and a positive LN on final pathology and the patient who later developed nodular pelvic side wall uptake as false-negative studies, the NPV of PET/CT-PSMA is 97.1%.
Figure 2.
18F-PSMA-1007 PET/CT of a 58-year-old patient with clinical stage T2b, PSA = 11 ng/mL, and ISUP 2. Increased uptake (SUVmax 27) is noted preoperatively in the left prostate (top row). His risks of positive lymph nodes were 18%, 7%, and 6% according to the Partin, MSKCC, and Briganti 2012 nomograms, respectively. Final pathology showed T2c, ISUP 3 with negative surgical margins. Twenty months postoperatively, PSA rose to 0.23 ng/mL. A second scan (bottom row) showed uptake in a 4 mm nodule in the left pelvic wall (SUVmax 4.7), suspected to represent an involved lymph node. Note the absence of urinary excretion of the tracer in both studies. ISUP = International Society of Urological Pathology; PSA = prostatespecific antigen; PSMA = prostate-specific membrane antigen; PET/CT = positron emission tomography/computed tomography.
4. Discussion
In this study, RP with PLND was performed in patients with intermediate (34) or high-risk (36) disease and PSMA-PET/CT studies negative for extraprostatic disease. Ignoring the PSMA-PET/CT findings, the expected number of patients with positive lymph nodes in this case mix should have been 7, 13, and 12 according to the Partin, MSKCC, and Briganti 2012 nomograms, respectively. Final pathology showed an involved LN in 1 patient, having a single node with a diameter of 1 mm. This is a significant difference between the expected and observed number of patients with positive LNs (p < 0.05). This suggests that in candidates for RP with negative PSMA-PET/CT for extraprostatic disease, the currently used nomograms for predicting LN involvement provide irrelevant results.
Prostate-specific membrane antigen-positron emission tomography/computed tomography in a patient in whom PSA rose to 0.23 ng/mL 18 months postoperatively demonstrated radioligand accumulation in a 4-mm pelvic side wall, which could represent an involved LN. Therefore, both patients with false negative PET were preoperatively classified in the intermediate-risk group. Considering this patient’s preoperative scan also as false negative, the negative predictive value of PET/CT-PSMA for predicting LN involvement in this study is 97.1%. This outstanding accuracy is better than the previously reported rates of 81%–89%.[12,14,16,17] This could be explained by the more homogeneous population in the current study, that is, the inclusion of candidates for RP with PSMA-PET/CT negative for extraprostatic disease. If verified in further studies, PLND can be spared in this population, saving operating room time and avoiding potential surgical complications.
The performance of sPLND in the current study with a median retrieve of 9 LNs is a drawback. When ePLND is performed, larger numbers of LNs are removed: 13 by Kopp et al. and 17 by Esen et al.[13,14] To overcome this limitation, all patients in the current study were followed for at least 6 months postoperatively and each PSA rise above 0.1 ng/mL triggered a sequential PSMA-PET/CT scan. As previously mentioned, extending sPLND (obturator and external iliac nodes) to ePLND (inclusion of the internal iliac nodes) or to super-extended PLND (adding the common iliac and presacral nodes) increases the number of retrieved nodes but also increases operation time, blood loss, complication rate, and length of hospital stay, without improving the rate of biochemical, cancer-specific, or overall recurrence.[3] In a prospective study of 123 patients, ePLND was performed on the right side and sPLND on the left. Lymph node metastases were found in 4 patients on the right side, in 3 patients on the left side, and in a single patient on both sides. Complications, including lymphocele, lower extremity edema, deep venous thrombosis, ureteral injury, and pelvic abscess, occurred 3 times more often on the right side (p = 0.08).[18]
Most reported PSMA-PET/CT were performed with 68Ga-PSMA-11. In the current study, 68Ga-PSMA-11 was employed in 13 patients and 18F-PSMA-1007 in 57 patients. 18F-PSMA-1007 offers several advantages, including a longer half-life and almost no urinary excretion, as depicted in Figure 2. This feature facilitates the detection of lesions close to the bladder. Indeed, Sprute et al. reported an NPV of 97.9% for pelvic LN involvement when using 18F-PSMA-1007, similar to the 97.1% reported here.[19]
5. Conclusions
In this study, PSMA-PET/CT was found to be highly accurate for ruling out LN involvement in candidates for RP. The results suggest that when PSMA-PET/CT shows no extraprostatic uptake, PLND can be omitted, even in patients with high-risk disease. The nomograms that were developed before the PET/CT-PSMA era are no longer useful for decision making.
Acknowledgments
None.
Statement of ethics
The study was conducted in accordance with the Declaration of Helsinki and approved by the Hadassah Medical Organization (HMO) IRB (# 0155-23). Because this was a retrospective study based on medical chart review and standard follow-up data, informed consent was waived by the Hadassah Medical Organization (HMO) IRB (# 0155-23).
Conflict of interest statement
The authors declare no conflicts of interest.
Funding source
None.
Author contributions
ONG: Concept, design, writing;
MO, SB-H: Concept, analysis of data;
TM: Analysis of data;
MD, GH: Concept critical review;
VY: Concept, writing, critical review;
All authors approved the final version.
Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Footnotes
How to cite this article: Gofrit ON, Orevi M, Ben-Haim S, Meuman T, Duvdevani M, Hidas G, Yutkin V. The relevance of nomograms for prediction of pelvic lymph node metastases in the prostate-specific membrane antigen (PSMA)-PET/CT era. Curr Urol 2025;19(5):353–356. doi: 10.1097/CU9.0000000000000290
Contributor Information
Marina Orevi, Email: marinaor@hadassah.org.il.
Simona Ben-Haim, Email: simonabh@hadassah.org.il.
Tzahi Meuman, Email: Tneuman@hadassah.org.il.
Mordechai Duvdevani, Email: moti_duv@yahoo.com.
Guy Hidas, Email: guyhidas@icloud.com.
Vladimir Yutkin, Email: Yutkin@hadassah.org.il.
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