Comparing the diagnostic value of ⁶⁸Ga-prostate-specific membrane antigen PET/CT and multiparametric MRI in pelvic lymph node metastasis of locally advanced prostate cancer

Introduction

Prostate cancer (PCa) is the most common malignant tumor of male urinary and reproductive system (1), which is one of the main causes of cancer-related death in elderly men. PCa is prone to lymph node or bone metastasis (2). Patients with locally advanced PCa (LAPC) is generally defined as those who have regional lymph node metastasis (LNM) or clinical stage T₃–T₄ without systemic metastasis, regardless of the level of prostate-specific antigen (PSA) or Gleason score (3,4). According to the clinical guidelines of the European Association of Urology (EAU), if the risk of nodal involvement calculated by nomogram is more than 7%, the patient is suspected LNM (5). For these patients, pelvic lymph node dissection (PLND) is considered as the “gold standard” for determining LNM of PCa. PLND can not only provide accurate lymph node pathological staging, but also remove potential LNM (6). Radical prostatectomy (RP) and PLND are commonly performed in patients with LAPC, especially those diagnosed with PLND before surgery. However, relevant studies have shown that PLND may increase the incidence of complications (such as organ damage, lymphatic fistula, etc.) (7), which increases the economic burden on patients. Therefore, it is crucial to find a non-invasive method for preoperative pelvic lymph node evaluation.

Computed tomography (CT), magnetic resonance imaging (MRI), and other imaging examinations take the size of lymph nodes as the diagnostic criteria for identifying metastatic lymph nodes. Multiparametric MRI (mpMRI) is a comprehensive evaluation of the lesions by multi-parameter and multi-sequence MRI, and has become a commonly used imaging method for the preoperative evaluation of PCa, which can well display the condition of the prostate capsule, to check whether PCa encroaches on the surrounding tissues and organs, and the metastasis of pelvic lymph nodes (8). However, the accuracy of mpMRI for the detection of pelvic lymph nodes is limited, not only small metastatic lymph nodes may be missed, but also false positive result may occur in the case of lymph node hyperplasia, which affects the treatment of PCa patients.

Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein composed of 751 amino acids in the form of monomer or dimer, which contains prostate extracellular segment, transmembrane segment, and intracellular segment. Its expression in PCa tissues is significantly higher than that in normal prostate tissues (9), and is positively correlated with Gleason score, PSA level, and other factors (10). It is a good target molecule related to PCa (11-13). ⁶⁸Ga-PSMA positron emission tomography (PET)/CT is a new imaging examination method based on ⁶⁸Ga nuclide labeled PSMA, which can accurately locate PCa tissues, and has become a hot spot in PCa diagnosis and treatment research (14).

This retrospective study analyzed 50 patients with LAPC who underwent preoperative ⁶⁸Ga-PSMA PET/CT and mpMRI examinations. The study aimed to compare the diagnostic value of the two methods in detecting pelvic LNM (PLNM) in PCa. We present this article in accordance with the TRIPOD reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-24-15/rc).

Methods

General information

We included 257 patients with PCa and performed post-surgical histopathological analysis to determine whether the patient was in the locally advanced stage of PCa. Ultimately, clinical data of 50 patients diagnosed with LAPC before surgery were retrospectively collected in Tongji Hospital from 2021-2023. The mean age of the patients was 65.5±10.3 years old, the total PSA (tPSA) before surgery was 30.7±12.3 ng/mL, and the Gleason score was 7 [7, 8]. All patients underwent ⁶⁸Ga-PSMA PET/CT and mpMRI before surgery. All the 50 patients underwent laparoscopic/robot-assisted laparoscopic RP and extended PLND (ePLND), the excision area of lymph node dissection included the ureter across the iliac vessel and was performed bilaterally. Lymph nodes adjacent to the external iliac artery, obturator artery, and internal iliac artery were respectively removed. Dissection of anterior sacral lymph nodes was not performed routinely. The boundaries of lymph node dissection were as follows: upper to the ureter across the iliac vessel, lower to the start of abdominal wall arteriovenous, outer to genitofemoral nerve, inner to internal iliac artery. The exclusion criteria were (I) pathologically confirmed non-LAPC; (II) patients who did not perform ⁶⁸Ga-PSMA PET/CT or mpMRI before surgery; and (III) patients who did not receive PLND during the operation. After operation, the patients were divided into clinical lymph node positive (cN+) and clinical lymph node negative (cN0) groups according to the results of pathological examination of lymph node. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology (No. 2019CR101) and individual consent for this retrospective analysis was waived.

⁶⁸Ga-PSMA PET/CT examination and image analysis

⁶⁸Ga-PSMA-617 was synthesized by automated labeling module of ITM (Munich, Germany). The radiochemical purity of the synthesized product was higher than 95%. Patients receiving ⁶⁸Ga-PSMA PET/CT were intravenously injected with ⁶⁸Ga-PSMA-617 at 1.8–2.2 MBq per kg of body weight, followed by PET/CT imaging for 1 to 1.5 hours, which were produced by General Electronic Healthcare located in Chicago, IL, USA.

The scanning adopted 120 kV voltage, 120 mA current, and 3.8 mm layer thickness. The scans covered the pelvis and prostate, and each bed was scanned for two minutes. The PET image after attenuation correction of CT data was reconstructed by the sequential subset maximum expected value selection method, and the multi-directional fusion image of CT, PET, and PET-CT was obtained. LNM of PCa is considered to occur when maximum standardized uptake value (SUVmax) >2.5 or the short diameter of the lymph node is more than 1.0 cm on ⁶⁸Ga-PSMA PET/CT.

mpMRI examination

The Avanto 1.5-T superconducting resonator of Siemens was used for magnetic resonance examination of the patients. Before the examination, the patient was given 15 mL glumine gadolinium penate intravenously with a syringe. The first scan was performed 20 seconds after the injection, and the scan lasted for 12–15 sessions. Before enhanced scanning, scanning was performed in four directions of prostate sagittal position, cross section, longitudinal relaxation position, and relaxation coronal plane, then localization scanning was performed in four directions, and magnetic resonance spectroscopy (MRS) was performed in these directions to scan the whole prostate. The scan sequences included transverse, coronal, and sagittal T2-weighted imaging (T2WI), transverse T1-weighted imaging (T1WI), adipose suppression T2WI, and diffusion-weighted imaging (DWI). Repetition time of scanning was 700 ms, echo time was 120 ms, excitation times were 6, reverse angle was 90°, layer thickness was 50 mm, and the total scanning time was 12 minutes. LNM of PCa is considered to occur when the short diameter of the lymph node is more than 1.0 cm on mpMRI.

Image analysis

⁶⁸Ga-PSMA PET/CT and mpMRI examination results were evaluated by two professional and senior nuclear medicine or imaging doctors without knowing the pathological diagnosis of patients, with visual analysis and semi-quantitative method. For those image results which were difficult to judge or with different opinions, a third experienced evaluator was invited to participate, and the final decision was made by combining opinions. mpMRI showed metastatic lymph nodes which were defined as locally enhanced or diminished abnormal signals. If there is LNM, the signal is bright and high on DWI and significantly low on apparent diffusion coefficient (ADC).

Statistical methods

Statistical analysis was conducted with SPSS (24.0) software. Statistical data conformed to normal distribution were described with mean ± standard deviation (SD), and inter-group comparison was conducted with t-test of two independent samples. For measurement data that did not conform to normal distribution, M (Q1, Q3) was used to describe them, and rank sum test was used for comparison between groups. Continuity check (Kappa test) was used to compare the consistency of the two imaging findings and postoperative pathological findings. Based on the number of patients who had lymphatic metastasis and the number of pelvic metastatic lymph nodes, chi-squared test was used to compare the sensitivity and specificity of local metastases detected by the two tests. The sensitivity and specificity of the two tests for the detection of local metastases were compared by chi-squared test. P<0.05 meant the difference was statistically significant.

Results

In this study, 50 patients underwent ⁶⁸Ga-PSMA PET/CT and mpMRI examinations, followed by laparoscopic/robot-assisted laparoscopic RP and ePLND, and none was converted to open surgery during the operation. The operation time was 116.3±29.3 min. The intraoperative blood loss was 90.1±36.3 mL, and the hospital stay was 7.1±1.9 days after the operation. Postoperative complications occurred in 12 cases, including postoperative fever in five cases, urine leakage in two cases, and lymphatic leakage in five cases, which were relieved after anti-infection, urethral catheter pulling, and drainage catheter indentation time extension (see Table 1 for details).

Postoperative pathological examination revealed that LNM was found in 16 patients, a total of 641 lymph nodes were dissected, including 63 metastatic lymph nodes. Fifteen patients were diagnosed with LNM with PSMA-PET, and 60 positive lymph nodes were detected. mpMRI diagnosed 11 patients with LNM and detected 41 positive lymph nodes. The number of removed nodes per patient was 12.82±3.71, and the number of removed nodes per patient was 3.93±2.19. In the diagnosis of PLNM of PCa, the detailed results of ⁶⁸Ga-PSMA PET/CT and mpMRI are shown in Table 2. The sensitivity, specificity, positive predictive value, and negative predictive value of ⁶⁸Ga-PSMA PET/CT diagnosis were as follows: 93.75%, 100.00%, 100.00%, 97.14%. The counterparts of mpMRI diagnosis were: 68.75%, 97.06%, 91.67%, 86.84%, both in sensitivity and negative predictive value, P<0.05, the difference was statistically significant, compared with both in specificity and positive predictive value.

According to the number of LNMs, the diagnostic efficacy of ⁶⁸Ga-PSMA PET/CT and mpMRI for PLNMs of PCa was analyzed, and the results are shown in Table 2. The sensitivity, specificity, positive predictive value, and negative predictive value of ⁶⁸Ga-PSMA PET/CT were: 95.24%, 100.00%, 100.00%, 99.48%; the sensitivity, specificity, positive predictive value, and negative predictive value of mpMRI were 65.08%, 99.13%, 89.13%, and 96.30%, respectively. Comparing the sensitivity of the two methods, P<0.05 meant that the difference was statistically significant. Conversely, for specificity, positive predictive value, and negative predictive value, P value >0.05 indicated that the difference was not statistically significant.

As is shown in Figure 1, a typical case showed that ⁶⁸Ga-PSMA PET/CT was significantly more sensitive than mpMRI in finding metastatic lymph nodes. The patient was a 68-year-old male with preoperative PSA 7.41 ng/mL and Gleason score of 4+5=9. Figure 1A,1B show ⁶⁸Ga-PSMA PET/CT detected right PLNM (arrow), while Figure 1C shows mpMRI did not detect PLNM. Postoperative pathological report showed PCa metastasis in right pelvic lymph nodes (3/3). Figure 1D shows the hematoxylin-eosin (HE) staining image of the lymph node detected by ⁶⁸Ga-PSMA-PET but omitted by mpMRI (×20).

Figure 1 Comparison of ⁶⁸Ga-PSMA PET/CT and mpMRI in detecting PLNM of PCa. (A) ⁶⁸Ga-PSMA PET image reveals one focally increased tracer uptake (black arrow) in the right pelvic region. (B) ⁶⁸Ga-PSMA PET/CT fusion image shows positive lymph node (SUVmax 7.3; white arrow) in the right pelvic region. (C) mpMRI image of the pelvic region is unremarkable. (D) The pathological result (HE staining, ×20) after PLND demonstrated PLNM in the right pelvic. PSMA, prostate-specific membrane antigen; PET, positron emission tomography; CT, computed tomography; mpMRI, multiparametric magnetic resonance imaging; PLNM, pelvic lymph node metastasis; PCa, prostate cancer; SUVmax, maximum standardized uptake value; HE, hematoxylin-eosin.

Discussion

PCa is a kind of solid malignant tumor with the highest incidence in males, and the incidence of PCa is increasing rapidly in China (11,15). Approximately 30–40% of newly diagnosed PCa patients in China are LAPC, which is characterized by poor prognosis and prone to recurrence and metastasis (LNM), and once a patient develops LNMs, the prognosis is usually poor. For LAPC patients, the choice of treatment plan is often controversial. Surgical treatment has certain advantages in the treatment of LAPC, and RP can be used as one of the options.

A variety of predictive models have been proposed for preoperative assessment of the risk of LNM in PCa. For example, 588 patients with localized PCa who underwent RP and ePLND were enrolled in a scientific research (6). Based on PSA, clinical stage, Gleason score and the proportion of positive needle number in prostatic puncture, the risk of LNM was predicted by a Briganti nomogram (6). The sensitivity, specificity, and negative predictive value of LNM were 87.8%, 70.3%, and 98.4%, respectively. The AUC value was 87.6%. ePLND is recommended for patients with a risk of LNM more than 5%, which plays a major role in guiding the selection of surgical methods for PCa patients. However, the predictive effect of this model needs further clinical verification.

mpMRI is the most commonly used imaging examination method for judging the tumor, node, metastasis (TNM) staging of PCa at present, which can well display the prostate capsule, to check whether cancer lesion encroaches on the surrounding tissues and organs, and the metastatic situation of pelvic lymph nodes. However, mpMRI mainly identify metastatic lymph nodes by lymph node size. Previous studies have shown that mpMRI has the disadvantage of insufficient sensitivity, which makes it easy to miss PLNM before surgery (16,17), and up to 30% of patients have no suspicious LNMs in preoperative CT or mpMRI. However, LNM was found in the ePLND (18). Meanwhile, mpMRI is often difficult to distinguish inflammatory lymph nodes and reactive hyperplasia lymph nodes from tumor metastases (19).

Therefore, finding an accurate way to identify and diagnose PLNM is of great significance for the selection of treatment methods and prediction of postoperative prognosis (20). In recent years, with the rapid development of nuclear medicine technology, ⁶⁸Ga-PSMA-PET has been increasingly used in the early diagnosis of PCa and the detection of postoperative metastases (LNM, bone metastasis, visceral metastasis), showing good sensitivity and specificity. PSMA is a type II transmembrane glycoprotein (21), and it has the characteristics of tissue specificity, and is a promising target molecule for therapy of PCa (11). It has the following advantages:

• PSMA is physiologically expressed in some human organs (such as prostate, kidney, small intestine, etc.), but the expression level in PCa tissues is 100–1,000 times higher than that in normal prostate tissues, and is positively correlated with the severity of PCa (such as stage and grade).
• When patients enter the stage of castration resistance, PCa cells will lose a lot of PSAs, while PSMA is still highly expressed. Due to the high expression of PSMA in LNM area, PSMA-PET has a great advantage in the diagnosis of PLNM in PCa.
• When PSMA ligand binds to its enzyme active region, it can migrate and stay in PCa cells after internalization, which makes its enzyme active region an ideal site for imaging studies (22,23). ⁶⁸Ga-PSMA PET/CT technique has good biological characteristics and half-life. By using radionuclide ⁶⁸Ga to label PSMA, relevant lesions (primary lesions, metastases) can be shown (13).

Our research found that compared with mpMRI, ⁶⁸Ga-PSMA PET/CT was more sensitive to the diagnosis of PLNM in patients with LAPC. Similar results have been found in other studies. Hövels et al. reported that the sensitivity of MRI and CT in the diagnosis of LNMs of PCa was about 40%, but 30% of patients had LNMs smaller than 5 mm, which was likely to cause patients’ disease recurrence (20,24). Abufaraj et al. retrospectively reviewed 149 high-risk PCa patients who underwent ⁶⁸Ga-PSMA-PET before RP, and found that ⁶⁸Ga-PSMA-PET had high diagnostic accuracy in monitoring regional LNM. Regional lymph node analysis in 65 patients showed that the sensitivity of the left and right lymph node monitoring reached more than 90% (25). All the above studies indicate that ⁶⁸Ga-PSMA-PET is expected to become an effective method for the early detection of metastatic lymph nodes in PCa, and provide assistance for the formulation of treatment strategies (20), so as to benefit PCa patients.

Overall, ⁶⁸Ga-PSMA PET/CT showed higher sensitivity and accuracy compared to mpMRI. Therefore, ⁶⁸Ga-PSMA PET/CT may be a more suitable approach for detecting PLNM in LAPC patients. highlighting the importance of utilizing advanced imaging techniques to accurately detect LNM in PCa patients which may have significant implications for treatment outcomes of LAPC patients.

However, the number of patients with ⁶⁸Ga-PSMA PET/CT and mpMRI examination included in this study was relatively small, which may have some influence on the results. Therefore, we will conduct prospective randomized controlled studies with a larger sample size to further confirm the research conclusions in the future.

Conclusions

To sum up, this study shows that for the detection of pelvic lymph nodes in patients with LAPC, the sensitivity of ⁶⁸Ga-PSMA PET/CT is higher than that of mpMRI, which is of great significance for preoperative assessment of PLNM and accurate staging, guiding surgeons to optimize treatment plans, and achieve personalized precision medicine.

Acknowledgments

Funding: This work was supported by the National Natural Science Foundation of China (No. 82173068 to Z.W.).

Footnote

Reporting Checklist: The authors have completed the TRIPOD reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-24-15/rc

Data Sharing Statement: Available at https://tau.amegroups.com/article/view/10.21037/tau-24-15/dss

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-24-15/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-24-15/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology (No. 2019CR101) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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