Article: Wehrmedizinische Monatsschrift 8/2018

The Role of PSMA PET/CT and PET/MRI in Diagnosing Prostate Carcinoma

Division VI, Bundeswehr Medical Service Headquarters¹, Koblenz (Chief of Division: Oberstarzt Dr. Thomas Harbaum), Bundeswehr Institute of Preventive Medicine², Andernach (Director: Oberstarzt Prof. Dr. Dr. Dieter Leyk), Department of Nuclear Medicine³, Department of Radiology and Neuroradiology⁴, Department of Urology⁵ of the Bundeswehr Central Hospital³, Koblenz (Commander and Medical Director: Generalarzt Dr. Norbert Weller)

Manuela A. Hoffmann¹,²,³, Helmut J. Wieler³, Kerstin Smolka⁴, Hans-Ulrich Schmelz⁵, Stephan Waldeck⁴

Summary

Prostate cancer (PCa) is the leading cancer in men in Europe. The department of Urology of the Bundeswehr Central Hospital in Koblenz has founded the certified PCa-Centre Koblenz-Mittelrhein to optimise diagnostics and treatment of patients with PCa. The introduction of prostate-specific membrane-antigen (PSMA) into the diagnostic process is a worldwide breakthrough for the work of nuclear medicine departments. 

The value of 68Ga-PSMA PET imaging as a diagnostic procedure for primary and recurrent PCa is assessed. The most important data from mostly retrospective studies currently available are discussed. The current knowledge on 68Ga-PSMA PET suggests that primary staging with PET/CT and/or PET/MRI is useful in patients with intermediate to high-risk PCa and that the combination with pelvic multiparametric (mp) MRI has the greatest impact on patient management. 68Ga-PSMA PET/CT is superior to 18F/11C-Choline PET/CT in primary and secondary staging. In patients with biochemical relapse, PET/CT positivity is directly associated with prostate-specific antigen (PSA) increase. 

Keywords: 68Gallium-PSMA, PET/CT, PET/MRI, PET-guided personalised therapy, prostate cancer 

Introduction

Prostate cancer (PCa) is the most common cancer to affect men in Germany. The estimated incidence for 2016 was 66,900 new cases. With 12,957 deaths, prostate cancer had the third highest mortality rate of all cancers in 2012 [7, 22]. Accurate diagnosis of suspected prostate carcinoma is critical when it comes to ensuring fast and curative care. In patients with presumed recurrent PCa following initial curative treatment, diagnostic imaging presents a challenge. 

Diagnostic imaging of prostate carcinoma

Primary diagnosis
PhotoFigure 1: PSMA PET/CT scans show multiple metastases in the spine and pelvis, some of them confluent, PSMA-avid, osseous. A diagnosis of PCa is still based primarily on non-specific screening methods such as PSA levels and digital rectal exams. Transrectal ultrasound-guided biopsy is often used to confirm a suspected clinical diagnosis. With this method, however, a carcinoma will remain undetected in 20–30% of cases and there is a high risk of undergrading, i.e. underestimating the aggressiveness of the tumour [5, 15, 31]. Another clinical problem is an increasing or elevated PSA level following a negative punch biopsy [14]. Recent studies have shown multiparametric MRI (mpMRI) to be superior to other diagnostic methods in patients with elevated PSA levels after negative biopsy results [5, 29, 32, 38]. The MRI protocol for the prostate usually combines thin-layered native T2-weighted sequences with diffusion-weighted sequences (DWI) followed by dynamic contrast-enhanced sequences with preferably isotropic voxels. Recent studies have shown mpMRI/ultrasound fusion-guided biopsies to achieve a significantly higher rate of detection of clinically relevant prostate malignancies than conventional diagnostic procedures [19]. There was no statistical significance in terms of differentiating between high-grade and low-grade carcinomas, however [18]. 

PhotoFigure 2: CT scans did not reveal any morphological abnormalities of pelvic lymph nodes which were, due to their high PSMA avidity, identified as suspicious only after the PET scan. There is growing evidence in the relevant literature that using PSMA PET helps further increase the reliability of diagnosis. PSMA is an integral membrane protein that, in prostate carcinoma cells, is expressed at levels up to 1,000 times that of normal prostate cells. PSMA expression is particularly elevated in high-grade carcinomas in patients with metastatic cancer and hormone-refractory prostate cancer (figure 1). As a result, PSMA has become a topic of great interest in the context of specific imaging and treatment of PCa. Working groups in Heidelberg [4, 10] and Munich [10] deserve credit for having introduced a diagnostic method that is now internationally recognised.

Expression of PSMA in the prostate increases with the aggressiveness of the tumour, whereas it is barely detectable in benign prostate tissue [8, 34, 37]. That is why hybrid methods are currently being developed to perform PSMA PET and mpMRI in a single-step exam in order to combine the high sensitivity of MRI with the metabolic assessment provided by PET [23, 26, 36]. This is particularly important with regard to undergrading of tumours as well as when it comes to optimising the TNM classification before treatment. In most cases, 68-Ga PSMA radiotracers are used and more recently F-18 PSMA radiotracers [35].

Diagnosing recurrence
Around 40% of patients who undergo local treatment with a primarily curative intent experience a recurrence of disease [30]. Most of these patients develop a biochemical recurrence, which means they have elevated PSA levels without showing any clinical evidence of metastases [9]. Biochemical tumour recurrence occurs in about 20–30% of patients after radical prostatectomy and in up to 60% after radiotherapy [12, 24]. In the event of such recurrence, standard sectional imaging with spiral CT or MRI is often of limited use, in particular when it comes to assessing pathologic lymph nodes. That is why substantial effort has gone into improving available imaging methods. In recent years, the relevant research has mainly focused on PSMA. 

The current German S3 Guideline on diagnosing PCa reflects this development and PSMA PET/CT is now an integral part of the diagnostic process [27, 28].

Significance of PSMA PET/CT
Since the introduction of the substance and method, a great number of publications have confirmed their clinical importance. In their study of traditional morphologic imaging in patients before radiotherapy, Giesel et al. [13] found that applying morphological CT criteria, mainly based on the size and shape of the lymph nodes, resulted in only 22% of PSMA-positive lesions being classified as suspicious for malignancy. In a comparison between PSMA PET/CT and 3D volumetric CT, two thirds of the patients were upstaged from cN0 to cN1. Previous studies had shown that high signal-to-background ratios are typical for PSMA PET/CT [2, 4, 25]. The study by GIESEL et al. [13] also demonstrated that the smallest PET-positive lesion, in this case a lymph node, had a short axis diameter of only 2.4 mm. This is almost the limit of what is physically feasible (1.7 mm) with this procedure. Especially for patients to be treated with salvage radiotherapy, PSMA PET/CT is of great significance. Salvage radiotherapy is recommended for patients with PSA levels < 0.5 ng/ml [16, 27]. PSMA PET/CT has been shown to help detect pathological contrast agent enhancement beyond the prostatic fossa even with such low PSA values. The most common locations were pelvic lymph nodes in about half of the patients with a positive PET/CT scan (figure 2). This would mean a change in treatment plan for about a quarter of all patients with low PSA levels referred for PSMA PET/CT [1, 11]. PSMA PET/CT will thus have an impact on patient management, helping to avoid, for example, ineffective radiotherapy and its sometimes considerable side effects or irradiation using radiation fields that include the affected lymph nodes. Recent studies have also shown 68Ga-PSMA PET/CT to be superior to 18F-Choline PET/CT in terms of image quality, higher specificity and good correlation of PSMA images with the Gleason score [17, 20].

Magnetic resonance imaging, and in particular multiparametric highfield 3T MRI, is currently the most sensitive morphological imaging method available on the market. Combining the high sensitivity of MRI with a highly specific tracer stands to reason. A direct comparison between PSMA PET/CT and PET/multiparametric MRI is therefore of considerable interest with regard to future studies [6]. It seems certain that, going forth, PET/CT and PET/MRI hybrid imaging systems will deliver better results than stand-alone morphological imaging [33].

Our studies comparing PSMA PET/CT and PET/MRI

Once PET/MRI had been introduced at the Bundeswehr Central Hospital in Koblenz, the findings in the first patients examined using both methods were compared.

Testing methods
PhotoFigure 3: PSMA PET/MRI scans show right-sided prostate cancer focus with considerably increased PSMA avidity. PET/CT images were produced with the Siemens Biograph 64 True Point PET/CT scanner (TrueV HD). Full-body scans were conducted 60 minutes after 68Ga-PSMA-11 injection (median 176 MBq, range 157–268 MBq). We received PSMA-11 from the Department of Nuclear Medicine at the University Medical Centre in Mainz and Advanced Accelerator Applications (AAA) in Bonn. PET/MRI scans with simultaneous acquisition of MRI sequences (non-contrast enhanced) were produced about 2 hours after injection using the Siemens 3 Tesla Biograph mMR hybrid system, immediately after PET/CT. The following sequences were used in the PET/MRI scan: transverse, coronal and sagittal T2 Turbo Spin Echo (TSE); coronal T1 TSE; sagittal T2; diffusion-weighted sequences (B50/500/1000); transverse short tau inversion recovery (STIR).

Results
PhotoFigure 4: PSMA PET/CT (fused image: middle) of left-sided infrapubic lymph node of 9 x 8 mm on non-contrast-enhanced CT (left) with considerably increased PSMA avidity observed on PET (right). A total of 193 PSMA PET/CT scans have been performed at the Department of Nuclear Medicine of the Bundeswehr Central Hospital in Koblenz since July 2015. Once PET/MRI had been established for standard use at the Bundeswehr Central Hospital in Koblenz, we were able to refer a first series of 34 patients for PET/MRI immediately following PET/CT (figure 3).

In this small group of patients, both types of scan revealed similar findings in 31 cases (31/34), with no additional pathological abnormality (lesion/lymph node/local recurrence) found in the second scan but not the first.

In three cases (3/34), there was a discrepancy between the two examinations; PET/CT was superior in two cases and PET/MRI in one case. 

In one patient, three prostate cancer foci with a high level of metabolic activity observed in PET/CT were not clearly identifiable in PET/MRI and intraprostatic PET/MRI findings were not assessable. 

PhotoFigure 5: PSMA PET/MRI (fused image: middle) of left-sided infrapubic lymph node (9 x 8 mm) hyperintense on T2-weighted MRI image (left, transverse STIR sequence) without evidence of increased PSMA avidity on PET (right). In a second case, a small left-sided infrapubic lymph node of 9 x 8 mm with considerably increased PSMA avidity observed in PET/CT could not be verified by PET/MRI due to halo artefacts. With an increased standardised uptake value (SUV) of 10.1 detected on the PET/CT scan, the lymph node was clearly suspicious for malignancy (figure 4). T2-weighted MRI showed hyperintensity of the lymph node, while PET/MRI did not reveal an increased PSMA avidity level due to extensive halo artefacts (figure 5). In the literature, halo artefacts are described as typical artefacts on PET/MRI that affect the detection of malign lesions located near the urinary bladder or kidneys [3, 21].

In the third case, the PET/MRI scan revealed four lymphogenic metastases, whereas PET/CT identified only two lymph node metastases.

Conclusions and outlook

Additional PET/MRI scans are important for our colleagues with a view to ensuring quality and confirming findings and we intend to conduct a prospective study to compare both methods, especially as there is currently little data available on this issue. The study should include newer algorithms for scatter corrections in PET/MRI to avoid halo artefacts. 

Key statements

  • mpMRI/ultrasound fusion-guided biopsies achieve significantly higher detection rates of clinically relevant prostate malignancies than conventional diagnostic procedures. 
  • The introduction of prostate-specific membrane antigen (PSMA) has been a global breakthrough in clinical diagnosis and treatment in nuclear medicine departments. 
  • PSMA PET/CT is considered an integral part of diagnosing recurrent PCa. 
  • PSMA PET and mpMRI complement each other in terms of sensitivity and specificity.


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Image source (all figures): Bundeswehr Central Hospital, Koblenz

Citation mode:
Hoffmann MA, Wieler HJ, Smolka K, Schmelz HU, Waldeck S: PSMA PET/CT and PET/MRI in prostate carcinoma diagnosis Wehrmedizinische Monatsschrift 2018; 62(8): 266 - 270.

For the authors:
Oberfeldarzt Dr. med. Manuela A. Hoffmann
Kommando Sanitätsdienst der Bundeswehr, Koblenz
Institut für Präventivmedizin der Bundeswehr, Andernach
E-Mail: manuela1hoffmann@bundeswehr.org

Date: 10/15/2018