Methods: We conducted a chart review from February 2015 to January 2017 of 50 male patients staged for prostate cancer using PSMA PET/CT and mpMRI who then underwent radical prostatectomy. Pre-operative PSMA PET/CT and mpMRI were paired with the corresponding histopathology. Correlations, sensitivity, and specificity were used for comparisons.
Results: A total of 81 lesions were confirmed by histopathology. Fifty index lesions were detected by histopathology, all of which were detected by PSMA PET/CT (100% detection), and 47 by mpMRI (94% detection). Thirty-one histologically confirmed secondary lesions were detected, 29 of which were detected by PSMA PET/CT (93.5% detection), and 16 by mpMRI (51.6% detection). PSMA had better sensitivity for index lesion localization than mpMRI (81.1 vs. 64.8%). Specificity was similar for PSMA PET/CT and mpMRI (84.6 vs. 82.7%).
SUVmax of index lesions ranged from 2.9 to 39.6 (M = 9.27 ± 6.41). Index lesion SUVmax was positively correlated with PSA (rho = 0.48, p < 0.001) and ISUP grade (rho = 0.51, p < 0.001).
Conclusions: PSMA-PET/CT provided superior detection of prostate cancer lesions with better sensitivity than mpMRI. PSMA-PET/CT can be used to enhance locoregional mpMRI to provide improved detection and characterization of lesions.
The Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) provides a uniform system for evaluating lesions suspicious for significant prostate cancer1. Multiparametric magnetic resonance imaging (mpMRI) provides valuable anatomical and functional information (through diffusion-weighted imaging and contrast enhancement) and is useful in aiding surgical approach in prostate cancer. The pooled sensitivity and specificity for mpMRI prostate cancer detection are 74% and 88% respectively2. Locoregional staging via mpMRI and other current imaging modalities suffer from a lack of accuracy. Assessment of lymph node involvement can be performed by both CT and mpMRI, but both have very low sensitivity3, 4. Bone scans to assess for bony metastases have low specificity3. Advances in PET technology, including radiotracers that target prostate cancer cells may be one way of enhancing current imaging modalities.
Prostate-specific membrane antigen (PSMA) is found in the cell membranes of several types of cells but becomes abnormally expressed in prostate cancer cells. It is a type II membrane protein with a 19-amino acid intracellular portion, a 24-amino acid transmembrane portion, and a 707 amino-acid extracellular portion5. The PSMA gene is usually not deleted in prostate cancer patients, rather dysplastic or neoplastic transformation leads to transfer of PSMA from the apical membrane to the luminal surface of prostatic ducts5. Unlike traditional FDG PET scans, which rely on glucose uptake in metabolically active cells indiscriminately, PSMA PET uses a fluorine- or gallium-based tracer with a PSMA ligand. The ligand attaches to PSMA and is selective for cells that have abnormal expression of PSMA6, 7. Abnormal PSMA expression has been demonstrated in the neovasculature of some nonprostatic tumors, and gallium radiotracer uptake can be increased by inflammation, which may explain the avidity of this non-prostatic cancers8, 9. While rare cases of incidental findings of PSMA-avid non-prostatic cancers have been reported, PSMA PET scans remain highly selective for prostate cancer when used in an appropriate clinical setting10–12. PSMA PET fused with concurrent CT is an emerging technology for the detection of prostate cancer that shows potential for improving the accuracy of prostate cancer staging using existing PET/CT scanners.
PSMA PET/CT can be used to locate lesions based on PSMA avidity. PSMA PET/CT can be used to identify the index carcinoma, secondary lesions, extra-prostatic disease, and regional and distant metastases. In an early prospective study of 20 patients, Rhee and colleagues found that PSMA PET/CT intraprostatic lesion localization was 49% sensitive and 95% specific, with 80% of clinically significant lesions being detected on PSMA PET/CT 13. Due to its infancy, there are currently no guidelines for the use of PSMA PET in the detection or staging of prostate cancer. We aimed to determine the association between 68Ga PSMA PET/CT and mpMRI in staging prostate cancer using histopathology from radical prostatectomy specimens as the gold standard.
Patients and methods
We conducted a chart review of patients identified by analysis of our prostate cancer database from February 2015 to January 2017 (24 months). Ethics approval was obtained from the Nepean and Blue Mountains Local Health District Human Research Ethics Committee. Patients were included in the study only if they had both using 68Ga PSMA PET/ CT and mpMRI and then proceeded to have a radical prostatectomy.
All patients had either been newly diagnosed with prostate cancer (primary staging, n = 48) or had a rising PSA following definitive radiotherapy with a view for salvage radical prostatectomy (n = 2).
All mpMRIs were performed by outpatient radiology providers whose 3 Tesla machines complied with PI-RADSv2 technical specifications. All MRIs were reported by radiologists proficient in PI-RADSv2 reporting methodology. All PSMA PET/CT scans were performed at our hospital on a Philips Gemini TF 64 PET/CT scanner with 68Ga-labeled PSMA ligand N,N′-bis[2-hydroxy5-(carboxyethyl)benzyl] ethylenediamine-N,N′-diacetic acid, or HBED-CC. PET image acquisition occurred over ~1 h and was fused with CT images acquired with the integrated 64 slice CT for lesion localization. All PSMA PET/CT scans were reported by a medical imaging specialist trained in PSMA PET/CT interpretation. All imaging was interpreted independently and without reference to histopathology results.
All radical prostatectomies were performed using the Da Vinci Si Robotic system (Intuitive Surgical, Inc.) by experienced robotic urological surgeons (>200 robotic caseloads per surgeon). All patients had lymph node dissections, the extent of which was based on each patient’s clinical scenario and intraoperative findings. Whole prostate histopathology specimens were processed and reported according to ISUP protocols by uropathologists from either a hospital-based or external pathology provider. All histopathology was reported independently and without reference to imaging results.
Clinically significant lesions were localized and recorded for each imaging modality and histopathology. mpMRI clinically significant lesions were defined radiographically according to PI-RADSv2 as volume ≥0.5cm3, and/or extraprostatic extension. PSMA PET clinically significant lesions were defined as areas of uptake with an SUVmax > 2.5. Patchy or diffuse areas of uptake were considered as separate lesions if these areas had an SUVmax > 2.5 and were discontinuous from any focal areas of uptake. SUV- max > 2.5 was chosen due to being in widespread use in PET interpretation14. Index lesions were defined at histological examination as the largest tumor focus. Other lesions within the same prostatectomy specimen were defined as secondary lesions.
The areas spanned by lesions on mpMRI and PSMA PET/ CT was compared using radical prostatectomy histopathology specimens as the gold standard. Index lesion detection and localization were the primary measures. The secondary measure was the detection of pelvic lymph node metastases. Each lesion was coded into eight possible slices of the prostate (Fig. 1: transverse (apex, mid, and/or base), sagittal (right, central, and/or left), and coronal (anterior and/or posterior). Areas were intentionally broad due to the limited soft-tissue anatomical detail possible with PET/CT. Index lesions were counted as “detected” as long as there was a corresponding lesion in one of the eight slices on histopathology and one or both imaging modalities. Index lesions could thus be detected but not fully localized if the lesion on imaging did not fully correspond to the positive slices on histopathology. For example, a lesion found to span two slices (e.g., apex and mid) on histopathology but was only seen in the apex on imaging would be “detected” but only partially localized.
Fig. 1: Index lesion localization. The prostate was divided such that each index lesion could be located in at least one each of transverse, coronal, and sagittal slices. Thus each lesion had at least three location markers. These divisions resulted in 400 possible locations.
Means and standard deviations are reported for normally distributed data, while medians and interquartile ranges are reported for non-normally distributed data. Spearman’s correlations, sensitivity, specificity, and McNemar’s tests were used for all comparisons. Spearman’s rho was chosen, as it is robust to skewed data15. Linear regression was used to produce models for estimate equations.
A total of 50 male patients were included in this study, with a mean age of 64.9 years (±5.6), and PSA of 10.6 (±8.1). The median time between PSMA PET/CT and surgery was 5 weeks (IQR 3-12 weeks), and the median time between mpMRI and surgery was 18 weeks (IQR 13–25 weeks). The median time between mpMRI and PSMA PET/CT was 12 weeks (IQR 7-15 weeks).
A total of 84 potential lesions were identified across all three modalities, with 81 lesions confirmed on histopathology. Characteristics of index lesions are shown in Table 1. Of the 50 index lesions confirmed on histopathology, PSMA PET/CT detected all 50, and 47 were detected by mpMRI (Fig. 2a). There were 31 histologically confirmed secondary lesions within the prostate (Fig. 2b), 29 of which were detected by PSMA PET/CT (with an additional 2 false positives), and 16 by mpMRI (with an additional 1 false positive). Index lesion localization sensitivity was similarly better for PSMA PET/CT than mpMRI (81.1% [95% CI 0.76–0.86] vs. 64.8% [95% CI 0.59–0.71], McNemar’s test p < 0.001). Both PSMA PET/ CT and mpMRI showed good specificity for index lesion localization (84.6% [95% CI 0.79–0.90] vs. 82.7% [95% CI 0.77–0.89]). PPV for PSMA PET/CT was 89.2 [95% CI 0.85–0.93] vs. mpMRI 85.4% [95% CI 0.80–0.90]. NPV for PSMA PET/CT was 74.2% [95% CI 0.68–0.81] vs. mpMRI 60.0% [95% CI 0.53–0.67].
Fig. 2: Index and secondary lesion detection. a.) Index lesions detected across three modalities. Of the 50 histologically confirmed index lesions, PSMA PET/CT detected all of them (100% detection rate) and mpMRI detected 47 (94% detection rate). b.) Secondary lesions detected across three modalities. Of the 31 histologically confirmed secondary lesions within the prostate, PSMA PET/CT detected 29 (94% detection rate), while mpMRI detected only 16 (52% detection rate).
While some patients showed good concordance between PSMA PET/CT and mpMRI, many did not. Figure 3 demonstrates an example of a patient for whom the PSMA PET/CT, mpMRI, and histopathology matched well, while Fig. 4 demonstrates an example of a patient for whom mpMRI missed the index lesion. The results below are reported for index lesions except where specified.
Fig. 3: Concordant imaging: a 73-year-old man with rising PSA 33 mg/mL, ISUP grade 3 (Gleason 4 + 3 = 7), with histopathology confirmed multifocal prostate acinar adenocarcinoma. a Transverse T2-weighted MRI image demonstrating an ill-defined focal hypointense area in the right posterolateral peripheral zone of the prostate gland. b Diffusion-weighted imaging (DWI) (B = 3000) and c apparent diffusion coefficient map confirm a mass with high cellularity. d PSMA PET/CT axial slice showing intense tracer uptake within the right lateral aspect of the gland. e Histopathology slides showing mid prostatic slice with tumor outlined with a marker.
Fig. 4: Discordant imaging: a 64- year-old man with rising PSA 4.5 mg/mL, ISUP grade 2 (Gleason 3 + 4 = 7), with histopathology confirmed multifocal prostate acinar adenocarcinoma. a Transverse T2-weighted MRI image demonstrating an ill-defined focal hypointense area in the left posterolateral peripheral zone of the prostate gland within the apex and mid gland. b Diffusion-weighted imaging (DWI) (B = 3000) and c apparent diffusion coefficient map confirm a mass with high cellularity. d Images D1–3 are consecutive axial T2 weighted images with the corresponding e images E1-3 PSMA PET/CT axial slices. There is intense tracer uptake within the right lateral aspect of the gland (SUVmax 4.6) (the index lesion on histopathology), however, only mild uptake in the left aspect of the gland (SUVmax 2.6) (the only lesion identified on mpMRI).
PSMA PET/CT background SUV ranged from 0.80 to 3.10 (M = 1.68 ± 0.41), and SUVmax of index lesions ranged from 2.9 to 39.6 (Mdn = 8.30). There was good differentiation between background SUV and lesion SUVmax (ρ = 0.24, p = 0.10). Index lesion SUVmax was positively correlated with PSA (ρ = 0.48, p < 0.001) and ISUP grade (ρ=0.51, p<0.001). There was a weak statistically significant correlation between PSA and ISUP grade (R = 0.28, p = 0.048). SUVmax of an individual index lesion could be predicted based on PSA, and SUVmax could be used to predict subsequent prostatectomy ISUP grade. Prediction equations were developed using linear regression to predict SUVmax based on PSA (Equation 1) and ISUP grade based on SUVmax (Equation 2).
Equation 1. Prediction of Index Lesion SUVmax Based on PSA
SUVmax = 0.324(PSA) + 5.734
Equation 2. Prediction of ISUP Grade Based on Index Lesion SUVmax
ISUP = 0.088(SUVmax) + 2.308
All patients had pelvic lymph node dissection (median 12 lymph nodes retrieved, range 3–22). For the six patients who had PSMA-avid pelvic lymph nodes (n=5) and/or mpMRI-detected lymphadenopathy (n=2), extended pelvic lymph node dissection was performed using templates. Only one of the patients with PSMA-avid lymph nodes was found to have nodal disease on histopathology, and one additional patient had nodal disease on histopathology with neither PSMA uptake nor mpMRI-detected lymphadenopathy (PSMA PET/CT 5 weeks and mpMRI 12 weeks prior to surgery). PSMA PET/CT thus had sensitivity of 50.0% [95% CI 0.0–1.00], specificity of 91.5% [95% CI 0.84–0.99], PPV of 20% [95% CI 0.0–0.55], and NPV of 97.7% [95% CI 0.93–1.00] for detecting pelvic lymph node spread. Neither patient with lymphadenopathy reported on mpMRI had nodal disease on histopathology (Table 2).
Forty-five patients (90%) were found to have multifocal disease on histopathology, and multifocal and unifocal disease both ranged in ISUP scores 2–5. PSMA predicted multifocal disease (defined as multiple discrete areas of focal uptake or large areas of patchy tracer uptake>2.5 SUVmax within the prostate) in 43 (86%) of patients, cor- responding to 88.9% sensitivity [95% CI 0.80–0.98], 40.0% specificity [95% CI 0.0–0.83], 93.0% PPV [95% CI 0.85–1.00], and 28.6% NPV [95% CI 0.0–0.62]. mpMRI predicted multifocal disease poorly (10% sensitivity [95% CI 0.0–0.21], 10% specificity [95% CI 0.0–0.23], 14.3% PPV [95% CI 0.0–0.29], and 6.9% NPV [95% CI 0.00–0.16]). PSMA PET/CT and mpMRI had similar spe- cificity for seminal vesicle invasion (SVI, 92.7% [95% CI 0.85–1.00] vs. 95.0% [95% CI 0.89–1.00], McNemar’s test p = 0.39), but PSMA PET/CT had poor sensitivity for SVI detection (11.1% [95% CI 0.0–0.32]) compared to mpMRI (75.0% [95% CI 0.45–1.00]).
Lesion localization of index tumors into eight slices as detailed above for 50 patients resulted in a total of 400 possible matches for each imaging modality. PSMA PET/ CT had better lesion localization sensitivity than mpMRI, which also failed to detect 18 histology-confirmed lesions (3 index, 15 secondary) in 16 separate patients (median 15 weeks to surgery, IQR 13.25–27.75). The index lesions missed by mpMRI were ISUP grades 2 (PSA 9.1), 3 (PSA 4.2), and 4 (PSA 6.2). Secondary lesions missed by mpMRI were ISUP grade 2 (n=15), 3 (n=8), 4 (n=4), and 5 (n = 7). One secondary lesion had a higher ISUP grade than its index lesion (ISUP 3 vs. 2).
Our study shows that 68Ga-HBED-CC PET PSMA/CT has a 100% detection rate for index lesions at radical prosta- tectomy, compared to 94% detection rate for mpMRI. For secondary lesions, PSMA PET/CT outperformed mpMRI with a detection rate of 93.5% vs. 51.6%. Lesion localization sensitivity was superior with PSMA PET/CT over mpMRI (81.1% [95% CI 0.76–0.86] vs. 64.8% [95% CI 0.59–0.71], p < 0.001) with good specificity from both (84.6% [95% CI 0.79–0.90] vs. 82.7% [95% CI 0.77–0.89]).
Use of the 68Ga-HBED-CC radiotracer in the detection of primary prostate cancer has not been firmly established, and as a result, there are very few cohorts in the literature who have undergone PSMA PET/CT and mpMRI prior to radical prostatectomy. We have shown that PSMA PET/CT can be reliably used to identify the prostatic index carcinoma, in some instances a secondary intra-prostatic lesion in the setting of loco-regional staging. PSMA PET/ CT has been primarily used in the detection of prostate cancer recurrence, however, our study shows its utility in pre-operative staging of intra-prostatic lesions 6, 16. Studies looking at the use of PSMA PET/CT for detection of lesions in patients with biochemical recurrence have demonstrated a relationship between PSA level and the likelihood of a positive PSMA PET study.17, 18 Our study has similarly shown a relationship between the PSA level and SUVmax of the detected lesions. Further research will be required to look at the relationship between PSA level and the possibility of PSMA PET/CT detecting a lesion in the pre-biopsy setting.
Our study suggests that PSMA PET/CT provided superior detection of intraprostatic lesions with a better sensitivity than mpMRI. This is consistent with findings from Giesel and colleagues, who reviewed ten patients who had PSMA PET and MRI as part of their primary staging 19. Another study by Eiber and colleagues also showed that PSMA PET outperformed mpMRI alone for the detection of prostate cancer (sensitivity 92% vs. 66%) and that the sensitivity for prostate cancer improved to 98% with PSMA PET/MRI, where the PET images are fused with mpMRI images. 20 PET imaging, particularly using PSMA ligands for prostate cancer, has been shown to be highly reproducible, with excellent results from a region of interest analyses and inter-rater reliability. 21, 22 This is in contrast to MRI, which despite a highly structured reporting system for prostate cancer, remains subject to significant inter-rater reliability and reproducibility limitations. 23, 24
Regional lymph node and extrapelvic metastasis detection were poorly evinced with mpMRI compared to PSMA PET/CT. This finding is also consistent with previous research that has shown that increasing the SUVmax threshold increases the accuracy of lymph node metastasis detection.14 PSMA PET/CT is unable to show detailed soft tissue anatomy, and as such mpMRI provides superior anatomic detail and detection of possible extracapsular extension or seminal vesicle invasion. This can be useful for surgical planning and decision making in the context of prostatectomy.
Our study is the second to correlate PSMA PET/CT and mpMRI with histopathology to compare the two imaging modalities, the first by Rhee and colleagues having only 20 patients and 50 clinically significant lesions (71 total lesions). 13 While our sample of 50 patients and 81 histopathology-confirmed lesions is moderate; it is one of the largest available cohorts of patients who have had PSMA PET/CT scans as part of their pre-operative prostate cancer staging. Similar to Rhee and colleagues, we found that imaging modalities resulted in several false positives and negatives, particularly false negatives for mpMRI. Our study demonstrated high concordance of PSMA PET/CT with histopathology for detection of index lesions and superior lesion localization over mpMRI.
All PSMA PET/CT imaging was performed by a single radiology provider and interpreted by a single medical imaging specialist. While this reduces variability in scan quality and readings, inter-rater reliability was not assessed. Patients were able to choose where they had their mpMRI performed. While mpMRI was performed by providers that all adhered to PI-RADSv2 technical specifications and reporting protocols, inter-institutional and inter-reader variability was not assessed. There were also multiple surgeons, with extended lymph node dissection being dependent on imaging, clinical scenario, and intraoperative findings. Our prediction equations should be interpreted with caution due to our relatively small sample size.
In our study, sensitivity for SVI was low in PSMA PET/ CT. This was possibly due to radiotracer excretion in the urinary bladder masking small areas of uptake in the seminal vesicles.
PSMA PET/CT and mpMRI each provide different invaluable pre-operative information, and as such both should be used in conjunction.25 Involvement of nuclear medicine specialists or radiologists trained in interpreting PSMA imaging at multidisciplinary team meetings may contribute to a more meaningful discussion of specific cases. Kinnear et al. found that over 90% of multidisciplinary team meeting decisions were implemented, making this an important venue for discussion of imaging findings in the context of clinical and patient-centered issues.26 A recent study of 595 prostatic lesions on mpMRI found that there were no differences in detection rate for in-gantry MRI- guided biopsy, transperineal biopsy with a known mpMRI lesion, and transrectal biopsy with known mpMRI lesion (the latter two of which are sometimes known as a cognitive MRI-guided biopsy).27 In that study, identification of an abnormal area was found to be more important than biopsy technique. Biopsy technique remains a contentious issue with other studies finding in-gantry MRI-guided biopsy more accurate than cognitive MRI-guided biopsy techniques, and we acknowledge that individuals vary in skills using different techniques.24 Given that PSMA PET/CT detects abnormal areas that are not detected on mpMRI, the addition of PSMA PET/CT has the potential to enhance biopsy detection rates regardless of biopsy technique chosen. There may also be a role for PSMA PET/MR hybrid imaging in the staging of prostate cancer, where facilities exist.13, 19, 20, 25 An early study of 20 patients showed superior detection of recurrent prostate cancer using PET/ MR over PET/CT28. Our study shows PSMA PET/CT provides superior detection of the index and secondary prostatic lesions, multifocal disease, and pelvic nodal disease over mpMRI alone.
Neither PSMA PET/CT nor mpMRI are currently listed under the Medical Benefits Scheme (FDG PET is listed, meaning it has a partial rebate unless the provider ‘bulk bills’ the patient, making it free to the patient). Patients pay fully out-of-pocket for both PSMA PET/CT and mpMRI, unless they have private insurance that covers the scan in whole or in part. At the time of writing, a PSMA PET/CT scan in Australia costs ~$600–800 at a private medical imaging provider. It is comparable to mpMRI, which costs approximately $600 according to an ongoing application to add mpMRI to the national Medical Benefits Scheme29. The cost of PSMA PET/CT for our patients has been borne by the hospital when the patient attends for bone scan and diagnostic CT (both of which have item numbers under the Medical Benefits Scheme). Actual costs in other countries will vary with the availability and utilization of technology as well as rates paid by insurance companies vs. state-based healthcare schemes.
There have been reports of PSMA-avid non-prostatic tumors in distant sites (i.e., false positives for prostate cancer but true positive for other cancers) likely due to increased PSMA expression in cancer neovasculature. In our study of intra-prostatic lesions, there were no false positives for primary lesions and only 2 false positives for intra-prostatic secondary lesions. PSMA PET/CT should be used in conjunction with biopsy and not for deciding to operate without histopathological confirmation. PSMA PET/CT can be performed around the same time as mpMRI without delaying surgery or biopsy. We, therefore, propose that PSMA PET/CT is an excellent add-on modality at this stage to aid in localizing prostate cancer lesions. Further studies are required to examine the use of PSMA to assess distant sites such as in bone and visceral metastasis.
Our study contributes to the growing research on PSMA PET in clinical practice and in particular for the localized detection of prostate cancer. PSMA PET/CT appears to be a useful adjunct to the detection and staging process that may supplement mpMRI in locating lesions. Although most centers do not have PET/MR machines, data from PET/CT and mpMRI can be used in conjunction to better detect and localize the lesion and thereby plan biopsy and surgical resection. More research is needed to further investigate the role of PSMA PET/CT in the detection and staging of prostate cancer.
Read More: A Commentary from an Associate Editor of PCAN - Henry Woo, MD
I. Berger1,2, C. Annabattula1,3, J. Lewis1, D. V. Shetty3, J. Kam1, F. Maclean4, M. Arianayagam1, B. Canagasingham1, R. Ferguson1, M. Khadra1,2, R. Ko1, M. Winter1, H. Loh3, C. Varol1
1. Nepean Urology Research Group, Nepean Hospital, Penrith, NSW, Australia
2. University of Syndey, Syndey, NSW, Australia
3. Department of Medical Imaging, Nepean Hospital Penrith, NSW, Australia
4. Douglas Hanley Moir Pathology, North Ryde, NSW, Australia
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