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More than 90% of primary prostate cancer lesions show moderate tohigh PSMA-expression levels by PSMA-PET 1 and many current researchesindicate that PET/MRI could be the single ideal imaging assessment for stagingof prostate cancer (PCa) patients 2–4. There are already proposed protocolspotentially viable for clinical routine application which match PI-RADS 2.0compliant multiparametric MRI acquisitions of the prostate bed to whole-bodyPSMA PET 4.The MRI component is the method of choice for more precisemorphologic evaluation, with higher spatial resolution and clearer anatomicdelineation of the prostatic fossa and surrounding anatomical structures 5,while PSMA PET is the superior modality for the detection of metastases tolocoregional and extrapelvic lymph nodes, bones and visceral organs 6.As a consequence, PSMA PET/MRI yields greater diagnostic accuracyfor PCa localization both compared with mpMRI and with PET imaging alone.These encouraging data indicate that hybrid imaging using morphologic,functional, and molecular information enhances the diagnostic performance inpatients with PCa for T, N and M staging.

2.T StagingMRI brings valuable conveniences over PET/CT due to the high softtissue contrast and offers the advantages of functional MRI techniques 5. Inturn, PSMA PET has a very specific molecular imaging target for PSMA-expressing tumor. Each component alone is capable of identifying tumor sitesthat would otherwise be missed or considered negative by the other technique.

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Thus, PSMA PET/MRI has superior sensitivity (76%) than both methods alone(58% and 64%) 2.Diffusion-weighted and dynamic contrast-enhanced MRI have potentialto furnish biological characterization of tumor aggressiveness in PCa patients.Recent data associate quantitative MRI parameters with Gleason score andtumor angiogenesis 7. Likewise, studies indicate that the intensity ofradiotracer accumulation in the primary tumor is correlated to PSA levels andGleason score (i.

e. the higher the PSA, Gleason scores and d’Amico riskscores, the PSMA uptake on PET) 8,9. The sum of those parameters couldprovide details about distinct tumor aggressiveness in different regionsthroughout the prostate gland and inside the same lesion. Accordingly,aggregating information of PMSA uptake, lesion cellularity, vascularpermeability and contrast media kinetics seemingly brings richer data for tumorcharacterization 10. This is of particular relevance when considering thepotential role of PSMA PET/MRI as a prebiopsy diagnostic tool which couldguide the sampling of the most aggressive sites. Hence, the method findindication for detection the intraprostatic malignant lesion in untreated patientswith newly diagnosed PCa 9.With regards to evaluation of tumor extent, extracapsular and seminalvesicle invasion, studies have shown promising results of PSMA PET.

Thoseparameters are major concerns for treatment planning. Curative surgery ispossible when none of these findings are present. Nerve-sparing surgicaltechniques might not be performed in men with extracapsular extension,leading to increased risk of urinary incontinence and erectile dysfunction afterprostatectomy, mainly when a bilateral technique is employed. There is alsoprofound impact on prognostication, since extracapsular extension and seminalvesicle invasion are both related to raised risk of recurrence and lymph nodeand bone metastases. PSMA PET/MRI can have an important impact in thelocal staging of PCa prior to radical prostatectomy 11.

Finally, adding the PET component could address two relatively commonshortcomings of MRI: reducing the limitation of the evaluation of patients whounderwent recent biopsies and increasing the performance of the assessmentof transition zone (TZ) lesions. With regard to the first issue, whereas functionalMR techniques such as DCE and DWI could potentially be flawed for pitfallsand artifacts due to prior biopsy, PSMA PET does not appear to be impaired bythose issues 10. In relation to the second matter, the imaging aspect of cancerlesions in the TZ may be confounded with other conditions on MRI, especiallybenign prostatic hypertrophy.

Albeit the peripheral zone is the most commonsite of PCa with up to 75–85% of the lesions, up to 25% of the patients mightdevelop tumors in the TZ. Hence, tumors in the transition zone of the prostateare often missed by MRI alone, raising the need for additional subsidy to thedetection of prostatic cancer in this location, and the aid required is fulfilled bythe presence or absence of PSMA uptake 12.The multimodal evaluation might facilitate biopsy orientation and lead toimpact on management, especially for prediction and monitoring of tumoraggressiveness for active surveillance, for determining more important targetswhen planning radiation therapy (dose escalations within a prostate clinicaltarget volume) 13 and for planning appropriate surgical technique andintraoperative management.

N StagingPSMA PET is decidedly superior to MRI in terms of identification of distantmetastases in patients with intermediate to high-risk PCa. As the methodbecomes more present in clinical setting, presumably many patients staged N0or M0 by current imaging evaluation will be more accurately staged as N1 or M113,14. Pretreatment staging with PSMA PET has the potential to beestablished as the standard of care regarding imaging for in those patients,since the success of therapy rely upon precisely to include sites of involvementthat would remain untreated when staging with conventional imaging 13.Involved lymph nodes are diagnosed by MRI when present morphologicchanges such as enlargement or round shape, whilst PSMA PET candemonstrate metastasis with the uptake of the tracer in morphologicallyunremarkable lymph nodes as small as 2 mm 1, even though also influencedby nodal size 15. A recent study reported that PSMA PET scans revealedpreviously unknown nodal involvement in 39% of the patients 14. Also,combination with multiparametric MRI are promising paths for obtainingadditional improvement of PET capabilities, to the greatest extent whencombined with PET/MRI, ultimately resulting in better nodal statusdetermination 13. A recent study including 130 patients revealed thattemplate-based analysis of sensitivity, specificity and accuracy for PSMA-PETwere 68.

3%, 99.1% and 95.2%, while for morphological imaging 27.3%, 97.1%and 87.6% were obtained 1.This is of paramount importance when curative local treatment of theprostate is considered, especially on external radiation therapy planning andsurgical resection.

With PSMA PET, a large number of patients may benefit ofdramatic changes in the contouring of the the targeted volumes and in theprescribed dose of radiation therapy. PSMA positive node tend to receivehigher doses than the adjacent pelvic nodal volumes. Also, clinical targetvolume (CTV) can be extended in order not to miss areas of disease notidentified by conventional studies and not targeted by consensus CTVs 13.M StagingIn intermediate and high-risk PCa patients, the current preoperativestaging for bone metastases includes MRI/CT and bone scintigraphy.As 99m Tc-MDP displays osteoblastic activity it demonstrates uptake inareas of degenerative and inflammatory diseases and fractures resulting in alow specificity for metastases 16. A recent investigation including 126 patientsrevealed sensitivities and specificities of osseous secondary involvement of98.

7-100 % and 88.2-100 % for PSMA PET and 86.7-89.3 % and 60.8-96.1 %for bone scan 17.

Another recent study reported that PSMA PET scansrevealed previously unknown distant metastatic disease in 16% of the patients14.Assessment of whole-body osseous tumor burden is also proposed byrecent studies which investigate the role of PSMA PET as an exploratoryimaging biomarker for prognostication and potential objective responseevaluation 18.The primary therapy for metastatic disease is androgen deprivationtherapy.

It remains nonetheless doubtful to many clinicians if patients withlimited metastatic disease (oligometastatic) should justifiably deserve a distinctapproach from the management of diffuse metastatic disease. Stereotacticradiosurgery or metastatectomy, in combination or not to androgen deprivationtherapy are being investigated by numerous studies 19. Therefore correctidentification of these patients is probably gaining importance and PSMA PETimaging likely emerges as an active player in this scenario 13.Finally, other distant lesions, including visceral and soft tissuemetastases that could easily be missed by conventional investigation arepotentially detectable by the whole body technique, such as pulmonary 3,9,genital and soft tissues lesions can be depicted by the method 9,20.

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