ABSTRACT
Introduction:
Gallium-68 prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) is being increasingly used in patients with prostate cancer (PCa) for the staging and detection of lymph node (LN) metastases, despite a lack of prospective, validated evidence. We aimed to investigate the relationship between the PSMA PET findings (maximum standardized uptake [SUVmax] value) and the final histopathology results (Gleason Grade [GG], and LN positivity) in patients undergoing radical prostatectomy.
Methods:
This is a single centre, prospective, observational study of 63 consecutive eligible patients treated at a tertiary care centre in India. Patients underwent 68Ga-PSMA PET computed tomography with fusion magnetic resonance imaging for staging, followed by a Transrectal ultrasound guided prostate biopsy. All patients underwent robotic-assisted radical prostatectomy with extended pelvic LN dissection as per the standard protocol. Clinical parameters and SUVmax values were collected and analysed.
Results:
The median preoperative prostate specific antigen (PSA) was 15.0 ng/ml (interquartile range: 9.4–28.0). A statistically significant correlation was observed between the PSA values and the SUVmax uptake (P < 0.001). Additionally, there was a statistically significant correlation between the SUVmax of the prostatic lesion and the GG on the radical prostatectomy specimens (P = 0.025), and SUVmax of LN and LN involvement (P < 0.001). The sensitivity and specificity of the 68Ga-PSMA PET scan were 77.8% and 88.7%, respectively.
Conclusions:
SUVmax of the PCa lesion and the GG Group on the final histopathology correlates significantly. There is an increased SUV uptake in Gleason’s Score (GS) 8, 9 tumours as compared to GS 6 and 7.
INTRODUCTION
The major challenge in the management of prostate cancer (PCa) lies in differentiating aggressive PCa from the indolent disease. It is best to refrain from overtreating patients with indolent PCa. Newer imaging techniques based on prostate-specific membrane antigen (PSMA) that specifically images and targets the prostate tumor cells at the molecular level can address this issue. Previous studies evaluating the PSMA expression found an increase in the PSMA expression in patients with advanced PCa. This relationship can be ideally used as a prognostic marker. Even at lower prostate specific antigen (PSA) values, Gallium-68-prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) demonstrates promising results for the detection of prostate lesions.[1] Currently, the 68Ga-PSMA PET is being used commonly as a diagnostic technique in cases of biochemical recurrence following the initial therapy.[2,3] It can also be used to locate lesions based on the PSMA avidity.[4] Studies have demonstrated superiority of 68Ga-PSMA-PET over the conventional imaging, and it is deemed well suited for the determination of primary PCa, and the detection of lymph node (LN) metastases.[5,6] This study aims to analyze the relationship between 68Ga-PSMA-PET findings (maximum standardized uptake [SUVmax] value) and the final histopathology results (Gleason grade [GG], and LN positivity) in Indian patients undergoing radical prostatectomy.
MATERIALS AND METHODS
This study was designed as a single-centre, prospective, observational study conducted at the department of Urology from June 2021 to June 2023.
All men aged >18 years, who had their prostates trans-rectally biopsied and were slated to undergo radical prostatectomy for adenocarcinoma PCa at our institution were included. Prostate biopsy was performed prior to the 68Ga-PSMA-PET scan. Patients with prior radiation therapy, those undergoing salvage prostatectomy, those with contraindications to PSMA PET-computed tomography (PET-CT)/magnetic resonance imaging (MRI) (such as claustrophobia, pacemakers, vascular clips, etc.), patients who would not be fit for radical prostatectomy, and patients who were unwilling to participate were excluded.
Based on the study by Koerber et al.,[7] which showed a 68% sensitivity of PSMA with the histological diagnosis, sample size calculation was carried out. This study complies with the Declaration of Helsinki and was approved by the Institutional Review Board (AMH-DNB-059/06-21). The authors confirm the availability of, and access to, all original data reported in this study.
Gallium-68 prostate-specific membrane antigen positron emission tomography– computed tomography with magnetic resonance imaging fusion imaging
Whole-body 68Ga-PSMA PET CT scan was performed using the Siemens Biograph mCT PET CT scanner with 64 slice CT 60 ± 10 min’ post-injection of 3–-5 mCi of 68GaPSMA. Simultaneously, a diagnostic contrast-enhanced CT was performed, and MRI was performed separately. The data obtained from PET/CT was combined with that obtained from the MRI and processed with the help of SYNGOVIA along with appropriate layouts. The SUVmax of the primary lesion and the pelvic LNs were calculated. All the images were analyzed by a single, experienced nuclear medicine specialist. Physicians were not masked to the patient characteristics as per the clinical practice at our institute. SUVmax offers greater reproducibility than SUVmean and does not depend on the size of the volume of interest, hence it was chosen as the primary variable for our study.
Radical prostatectomy
Robotic-assisted radical prostatectomy with extended pelvic lymph node dissection (EPLND) was performed on all patients diagnosed with PCa. All surgeries were handled by a single experienced surgeon. The standard anterior approach was used. In each case, the EPLND was used to stage the disease. EPLND entailed the removal of the nodes overlying the external iliac artery and vein, cranially and caudally placed in relation to the obturator nerve in the obturator fossa, and medial or lateral to the internal iliac artery.
Histopathological examination
Radical prostatectomy specimens were reviewed by a single experienced pathologist. The International Society of Urological Pathology (ISUP)[8] 2014 grade group system and Current AJCC 8th edition were used to report the histopathological results and staging.
SUVmax of the prostatic lesions and LN were determined and compared with the post radical prostatectomy Gleason grade (GG) of the specimen, and LN respectively.
Statistical analysis
Statistical analysis was performed using the SPSS (IBM SPSS Statistics for Macintosh, Version 28.0. IBM Corp. Armonk, NY, USA). The normality of continuous variables was tested using the Shapiro–Wilk test. Continuous variables were presented as either mean ± standard deviation or median with interquartile range (IQR). Categorical variables were presented as percentages and frequencies. McNemar’s Bowker test was used to determine the proportion changes between the baseline and the final visit. The Kruskal Wallis test was employed to identify significant changes in the SUVmax lesion and SUVmax of LN between various scores, grade and PSA. Mann–Whitney U test was performed to determine significant differences in the SUVmax values of the lesion and the LN. Sensitivity (Sn), Specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) were calculated, and receiver operator characteristic (ROC) curve was plotted. P < 0.05 was considered as statistically significant.
RESULTS
All patients completed the study. The mean age of the cohort was 67.4 ± 7.1 (range 51–80) years and the majority of the patients were between 61 and 70 years (44.4%). 19% (n = 12) and 36.5% (n = 23) of the patients were between the 51 and 60 and the 71–80-year age group, respectively. Among the study participants, 76.2% of patients presented with lower urinary tract symptoms and 23.8% patients were incidentally diagnosed with PCa after a prostatic biopsy for elevated serum PSA. Two patients had history of TURP in the past.
In our study population, the preoperative median PSA was 15 ng/ml (IQR 9.4–28.0). We divided PSA values into three categories, viz., <10, 10–20, and >20. The corresponding frequencies are shown in Table 1. The maximum PSA level was 207 ng/ml with SUVmax value of 5 while the minimum PSA level was 4.8 ng/ml noted in two patients with corresponding SUVmax values of 3 and 5.8. We observed a median PSA of 14 (IQR 10.3–18.5) in Gleason’s Score (GS) 6, 10 (IQR 8.9–21.2) for GS 7, 12.8 (IQR 9.3–19.2) for GS 8, 25.4 (IQR 14.5–66.0) for GS 9 and 19.5 (IQR 13.7–36) for GS 10.
Table 1.
Maximum standardized uptake values in different clinical parameters1
| Clinical Parameters | SUVmax Lesion | SUVmax Lymph Node | ||
|---|---|---|---|---|
|
| ||||
| Median (IQR) | P | Median (IQR) | P | |
| Serum PSA | ||||
| <10 (n=16) | 4.8 (2.9-5.6) | 0.001K | 0.4 (0.2-0.7) | <0.001K |
| 10-20 (n=22) | 6.1 (2.9-11.1) | 0.4 (0.3-0.9) | ||
| >20 (n=25) | 12.9 (6.1-20.0) | 0.9 (0.5-1.9) | ||
| Gleason Score | ||||
| 6 (n=18) | 3.7 (2.1-6.5) | 0.017K | 0.3 (0.2-0.43) | <0.001K |
| 7 (n=29) | 6.7 (3.4-16.1) | 0.4 (0.3-0.85) | ||
| 8 (n=6) | 13.6 (7.2-16.5) | 0.9 (0.6-4.3) | ||
| 9 (n=10) | 12.6 (5.5-17.6) | 1.7 (0.9-5.7) | ||
| Grade Group | ||||
| 1 (n=18) | 3.7 (2.1-6.4) | 0.025K | 0.3 (0.2-0.4) | <0.001K |
| 2 (n=20) | 5.4 (3.2-8.9) | 0.4 (0.3-0.8) | ||
| 3 (n=9) | 10.2 (3.6-17.3) | 0.8 (0.2-0.9) | ||
| 4 (n=6) | 13.5 (7.2-16.5) | 0.9 (0.6-4.2) | ||
| 5 (n=10) | 12.6 (5.5-17.6) | 1.7 (0.9-5.7) | ||
| Gleason Score | ||||
| 6 & 7 (n=47) | 5.2 (3-10.1) | 0.007M | 0.4 (0.3-0.8) | <0.001M |
| 8 – 10 (n=16) | 13.2 (6.2-16.7) | 1.2 (0.8-4.4) | ||
| Lymph Nodes | ||||
| Non-involved (n=53) | 5.9 (3.1-14.8) | 0.452M | 0.4 (0.3-0.8) | <0.001M |
| Involved (n=10) | 8 (4.7-14.1) | 2 (1-7.7) | ||
KKruskal Wallis test; MMann Whitney U test; Bold face indicates statistical significance
Similarly, we categorised patients into groups based on the ISUP grading system and the frequency is displayed in Table 1.
Maximum standardized uptake in prostatic lesions and pelvic nodes
SUVmax of the prostate lesions and the pelvic nodes were measured in all the patients. Correlation of SUVmax with the various parameters is shown in Table 1.
Correlation between PSA and maximum standardized uptake
The PSMA tracer uptake (Median SUVmax) significantly increased with the increasing levels of PSA groups viz < 10, 10–20, >20 ng/ml (P < 0.001 as per Wilcoxon signed rank test).
Correlation of maximum standardized uptake lesion, Gleason score
As per the Kruskal–Wallis Test, the correlation between SUVmax of the prostatic lesion and the GS of radical prostatectomy specimen was statistically significant (P = 0.017). Also, in the subgroup analysis between GS 6, 7 (group 1) and GS 8, 9 (group 2), correlation between the SUVmax of the prostatic lesion and the GS of the radical prostatectomy specimen reached a significant level (P = 0.007).
Correlation of maximum standardized uptake and Gleason grade
The correlation between SUVmax of the prostatic lesion and GG of the radical prostatectomy specimens was found to be significant, as per the Kruskal–Wallis Test (P = 0.025) as shown in Figure 1.
Figure 1.
Box plot of maximum standardized uptake and Gleason grade
Correlation of maximum standardized uptake of lymph node and nodal involvement
On the histopathology examination, a total of 9 patients had lymph nodal involvement by the PCa. A statistically significant correlation between the SUVmax of the LNs and LN involvement was seen, using the Mann–Whitney Test (P < 0.001). Nine patients with malignant LN involvement had median SUVmax of 2 (IQR 1.3–4.5), as shown in Figure 2. This group had a minimum SUVmax of 0.9 and a maximum of 19. In 55 patients, LNs were not involved. They had a median SUVmax of 0.4 (IQR 0.3–0.8), minimum SUVmax of 0.1 and maximum of 9.5.
Figure 2.
Box plot of maximum standardized uptake of noninvolved and involved lymph node
As per the ROC curve, the cut-off of SUVmax was 0.85 (95% CI), values above which suggest LN involvement on the histopathological examination. As per 0.85 as the cut off with a 95% confidence interval, we calculated the Sn, Sp, PPV, NPV of PSMA-PET as 77.8% (75.6–79.9), 88.7% (81.5–95.9), 53.8% (52–55.6) and 95.9% (93.5–98.3), respectively.
DISCUSSION
Results of our study demonstrate the clinical utility of 68Ga-PSMA-PET scan in patients with PCa to detect, and stage suspicious prostatic lesions. The 68Ga-PSMA-PET scan was able to detect lesions at low PSA levels. A statistically significant correlation was observed between the PSA values and the SUVmax similar to the studies by Koerber et al.,[7] and Uprimny et al.[9]
Correlation of maximum standardized uptake of primary lesion with Gleason score and grade
SUVmax values were varied in different GS and GG. Correlation between the SUVmax of the prostatic lesion and the GS and GG on the radical prostatectomy specimen reached a significant level with P = 0.017 and 0.025, respectively. Expression of the PSMA in PCa cells and SUVmax uptake could be an independent risk factor for high-grade PCa. Median SUVmax were 3.7, 5.4, 10.2, 13.5 and 12.6 for GG 1, 2, 3, 4 and 5, respectively. Median SUVmax increased as the grade increased. However median SUVmax was lower in GG-5 as compared to GG-4. This different behaviour of GG-5 PCa can be due the poor differentiation or genetic heterogeneity. In subgroup analysis between GS 6, 7 (group-1) and GS 8, 9 (group-2); the correlation between SUVmax of the prostatic lesion and the GS of radical prostatectomy specimen reached a significant level (P = 0.007).
In a retrospective study by Koerber et al.[7] that assessed 04 newly diagnosed patients with PCa, lesions with GS scores 6, 7a, 7b, 8, 9 and 10 showed median SUVmax values of 4.62, 5.56, 11.56, 13.94, 16.99 and 16.88, respectively. PCa with high GS (8-10) showed a statistically significant higher PSMA uptake (median SUVmax of 16.29) compared to the tumours with a GS of 6 or 7 (median SUVmax of 6.28; P < 0.001). However, in the same study in the subgroup analysis of 28 patients undergoing radical prostatectomy, the correlation between the GS and SUVmax did not reach a significant level (P = 0.142). They observed a median SUVmax of 8.32 and 16.64 for GS-7 and GS 8–10 group, respectively. In the retrospective study by Kallur et al.[10] that evaluated 262 patients, the level of 68Ga-PSMA positivity did not change with GS. In this study, a cut-off value of SUVmax > 4 was considered positive. In the retrospective study by Uprimny et al.,[9] when the SUVmax values for patients who underwent radical prostatectomy were compared to conclusive postoperative histology findings (n = 49), it was discovered that there was a statistically significant correlation (p 0.001) between the median SUVmax and GS: a median SUVmax of 6.8 in the group with GS 6 and 7 (range 2.7–35.1), and a median SUVmax of 19.5 in GS 8–10 tumours (range 5.3–65). In our study the median SUVmax were 5.8, 5, 7.35, 10.4 and 7.3 for GS 6, 7a, 7b, 8 and 9, respectively. In the above-mentioned study also, the median SUVmax were 5.9, 8.3, 8.2, 21.2, 22.8, 17.7 for GS 6, 7a, 7b, 8, 9 and 10, respectively, which are comparable to our study. In the subgroup analysis, the correlation between SUVmax of the prostatic lesion and the GS of radical prostatectomy specimen reached a significant level (P = 0.014) similar to that reported by Uprimny et al. (P = 0.001).
In a recent study by Vetrone et al.[11] the PSMA PET parameters of patients with high-risk PCa were compared with the histopathological parameters and immunohistochemistry and a positive correlation between the tumour volume and the total lesion on PSMA PET with the adverse parameters like cribriform pattern or lymphovascular invasion was found. In our study the SUV max was the primary tool with which the final histopathological outcome was assessed.
In a study by Duan et al.[12] 68Ga-RM2 PET (gastrin-releasing peptide receptor antagonist) accurately detected intermediate- and high-risk cancers with higher specificity as compared to mpMRI and similar to the performance of 68Ga-PSMA PET.
Correlation of maximum standardized uptake of lymph nodes with metastatic lymph nodal involvement
PSMA uptake defined as PET-positive was further evaluated by quantitative analyses comparing SUVmax values in suspicious lesions against the SUV uptake in the areas of normal PSMA biodistribution. Typically, studies did not assign a “cut-off” SUVmax value to denote PET positivity, except the study by Sterzing et al.[13] who diagnosed LN as PET-positive if the SUVmax was greater than >2.0. This cut-off was chosen after evaluating the blood pool remainder at 60 min post-injection in the aorta, which was found to be a mean SUVmax of 1.49 ± 0.49. Similarly, based on their analysis, van Leeuwen et al. concluded that a threshold SUVmax of 2.0 would have a 4% false-positive rate, and would detect 92% of the lymph node metastases.[14]
Statistically significant correlation was seen between SUVmax of the LN and LN involvement using the Mann–Whitney Test (P < 0.001). As per the ROC curve, 0.85 was seen as the cut-off and with this cut-off value, the PET Sn, Sp, PPV and NPV were 77.8%, 88.7%, 53.8% and 95.9%, respectively. However, SUV max cutoff for predicting the LN metastasis is low in our study and it could be a consequence of the relatively small number of patients with LN positive disease in the study cohort. Also, the expression of PSMA receptors can be different in different sets of populations (South Asians versus Caucasians).
In the study by Uprimny et al.,[9] out of a total of 82 patients, LN with pathologic 68Ga-PSMA uptake consistent with metastases were found in 24 patients (26.7%). Their median SUVmax was 10.6 (range: 3.1–90.6) and the median diameter was 10.9 mm (range: 3.9–32.9). Median SUVmax in patients with LN metastases was greater than that in patients without malignant LN involvement (18.7 vs. 9.7) and the difference was statistically significant (P = 0.001).
Herlemann et al. performed a prospective study of 34 patients for nodal staging using the 68Ga-PSMA-PET/CT prior to the lymph node dissection (LND) in patients with PCa. They concluded that 68Ga-PSMA-PET/CT provides accurate nodal staging prior to the LND. For 68Ga-PSMA-PET/CT the Sn, Sp, PPV and NPV for detection of LN metastases were 84%, 82%, 84% and 82%, respectively.[13]
There are some limitations of our study including small sample size. Also, the lack of comparison of SUVmax with the mpMRI is a drawback of the study.
CONCLUSIONS
SUVmax of the PCa lesion correlates significantly with the GG on the final histopathology. There is increased SUV uptake in GS 8, 9 tumours as compared to GS 6 and 7. Also, the PSMA-PET is excellent at detecting LN metastases and the SUVmax of the LN correlates with LN positivity. Therefore, PSMA-PET can be helpful in risk stratification and prognostication.
We recommend PSMA-PET CT/MRI for the primary staging in newly diagnosed PCa patients preferentially with a GS >7 in the Indian population especially for the LN metastases.
Conflicts of interest
There are no conflicts of interest.
Funding Statement
Nil.
REFERENCES
- 1.Afshar-Oromieh A, Zechmann CM, Malcher A, Eder M, Eisenhut M, Linhart HG, et al. Comparison of PET imaging with a (68)Ga-labelled PSMA ligand and (18)F-choline-based PET/CT for the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2014;41:11–20. doi: 10.1007/s00259-013-2525-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Hofman M. PSMA PET/CT for staging and treatment of prostate cancer. Clin Adv Hematol Oncol. 2019;17:370–3. [PubMed] [Google Scholar]
- 3.Hruby G, Eade T, Emmett L, Ho B, Hsiao E, Schembri G, et al. (68) Ga-PSMA-PET/CT staging prior to definitive radiation treatment for prostate cancer. Asia Pac J Clin Oncol. 2018;14:343–6. doi: 10.1111/ajco.12872. [DOI] [PubMed] [Google Scholar]
- 4.Hicks RM, Simko JP, Westphalen AC, Nguyen HG, Greene KL, Zhang L, et al. Diagnostic accuracy of (68)Ga-PSMA-11 PET/MRI compared with multiparametric MRI in the detection of prostate cancer. Radiology. 2018;289:730–7. doi: 10.1148/radiol.2018180788. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Maurer T, Gschwend JE, Rauscher I, Souvatzoglou M, Haller B, Weirich G, et al. Diagnostic efficacy of (68) gallium-PSMA positron emission tomography compared to conventional imaging for lymph node staging of 130 consecutive patients with intermediate to high risk prostate cancer. J Urol. 2016;195:1436–43. doi: 10.1016/j.juro.2015.12.025. [DOI] [PubMed] [Google Scholar]
- 6.Giesel FL, Sterzing F, Schlemmer HP, Holland-Letz T, Mier W, Rius M, et al. Intra-individual comparison of (68)Ga-PSMA-11-PET/CT and multi-parametric MR for imaging of primary prostate cancer. Eur J Nucl Med Mol Imaging. 2016;43:1400–6. doi: 10.1007/s00259-016-3346-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Koerber SA, Utzinger MT, Kratochwil C, Kesch C, Haefner MF, Katayama S, et al. (68)Ga-PSMA-11 PET/CT in newly diagnosed carcinoma of the prostate: Correlation of intraprostatic PSMA uptake with several clinical parameters. J Nucl Med. 2017;58:1943–8. doi: 10.2967/jnumed.117.190314. [DOI] [PubMed] [Google Scholar]
- 8.Epstein JI, Egevad L, Amin MB, Delahunt B, Srigley JR, Humphrey PA, et al. The 2014 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma: Definition of grading patterns and proposal for a new grading system. Am J Surg Pathol. 2016;40:244–52. doi: 10.1097/PAS.0000000000000530. [DOI] [PubMed] [Google Scholar]
- 9.Uprimny C, Kroiss AS, Decristoforo C, Fritz J, von Guggenberg E, Kendler D, et al. (68)Ga-PSMA-11 PET/CT in primary staging of prostate cancer: PSA and Gleason score predict the intensity of tracer accumulation in the primary tumour. Eur J Nucl Med Mol Imaging. 2017;44:941–9. doi: 10.1007/s00259-017-3631-6. [DOI] [PubMed] [Google Scholar]
- 10.Kallur KG, Ramachandra PG, Rajkumar K, Swamy SS, Desai I, Rao RM, et al. Clinical utility of gallium-68 PSMA PET/CT scan for prostate cancer. Indian J Nucl Med. 2017;32:110–7. doi: 10.4103/0972-3919.202255. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Vetrone L, Mei R, Bianchi L, Giunchi F, Farolfi A, Castellucci P, et al. Histology and PSMA expression on immunohistochemistry in high-risk prostate cancer patients: Comparison with (68)Ga-PSMA PET/CT features in primary staging. Cancers (Basel) 2023;15:1716. doi: 10.3390/cancers15061716. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Duan H, Baratto L, Fan RE, Soerensen SJ, Liang T, Chung BI, et al. Correlation of (68)Ga-RM2 PET with postsurgery histopathology findings in patients with newly diagnosed intermediate- or high-risk prostate cancer. J Nucl Med. 2022;63:1829–35. doi: 10.2967/jnumed.122.263971. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Sterzing F, Kratochwil C, Fiedler H, Katayama S, Habl G, Kopka K, et al. (68)Ga-PSMA-11 PET/CT: A new technique with high potential for the radiotherapeutic management of prostate cancer patients. Eur J Nucl Med Mol Imaging. 2016;43:34–41. doi: 10.1007/s00259-015-3188-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.van Leeuwen PJ, Emmett L, Ho B, Delprado W, Ting F, Nguyen Q, et al. Prospective evaluation of 68Gallium-prostate-specific membrane antigen positron emission tomography/computed tomography for preoperative lymph node staging in prostate cancer. BJU Int. 2017;119:209–15. doi: 10.1111/bju.13540. [DOI] [PubMed] [Google Scholar]