Editing Prostate Cancer: Diagnosis and evaluation (section)

===== <span style="color:#ff0000">Magnetic Resonance Imaging (MRI)</span> =====
* See [https://www.youtube.com/watch?v=TfUt-Ai8DF4 Video on Approach and Principles to Prostate MRI]
*'''MRI uses strong magnetic fields and the electromagnetic properties of hydrogen protons to generate the signal that is used to create images[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503950/#]'''
**Signal intensities vary based on the hydrogen content of the tissue
**For details, see [https://pubmed.ncbi.nlm.nih.gov/16009826/ Pooley, Robert A.] "Fundamental physics of MR imaging." ''Radiographics'' 25.4 (2005): 1087-1099.

====== <span style="color:#ff0000">Imaging sequences</span> ======
* Sequences relevant for prostate imaging
**T1-weighted imaging (T1WI)
**T2-weighted imaging (T2WI)
**Diffusion weighted imaging (DWI) with apparent diffusion coefficient (ADC) maps
**Dynamic contrast enhanced (DCE) imaging
**Magnetic resonance spectroscopic imaging (MRSI)
*Multi-parametric (mpMRI) is the combination of multiple MRI sequences
*'''<span style="color:#ff0000">In prostate cancer, the primary diagnostic parameters are (2):</span>[https://pubmed.ncbi.nlm.nih.gov/31392526/]'''
**'''<span style="color:#ff0000">T2WI</span>'''
**'''<span style="color:#ff0000">DWI with ADC maps</span>'''
* '''<span style="color:#ff0000">T2WI</span>'''
** Captures the movement of protons in the xy-axis (transverse)
** '''<span style="color:#ff0000">Primary uses (3):</span>'''
**#'''<span style="color:#ff0000">Visualization of zonal and anatomical features of the prostate.</span>'''
**#*See [https://www.researchgate.net/figure/Zonal-prostate-anatomy-on-axial-T2-weighted-MRI-image-peripheral-zone-PZ-and_fig1_346570342 Figure]
**#'''<span style="color:#ff0000">Optimal sequence in establishing the anatomic relation of the tumor with critical structures, such as the prostatic capsule and neurovascular bundles</span>'''.[https://pubmed.ncbi.nlm.nih.gov/26594835/]
**#'''<span style="color:#ff0000">Optimal sequence to evaluate lesions in the transition zone[https://pubmed.ncbi.nlm.nih.gov/31392526/]</span>'''
** '''<span style="color:#ff0000">Signal intensity</span>''' 
***'''<span style="color:#ff0000">High intensity</span>'''
****'''<span style="color:#ff0000">Fluids (CSF, urine)</span>'''
****'''<span style="color:#ff0000">Fat</span>'''
****'''<span style="color:#ff0000">Normal peripheral zone (due to its high water content)</span>'''
****'''<span style="color:#ff0000">Seminal vesicles</span>'''
***'''Intermediate intensity'''
****'''Central zone'''
*****Clinical implication: differential diagnosis of intermediate/low intensity lesions on T2 at the base of prostate and paramedian includes central zone that is being pushed out by BPH nodules of transition zone or cancer
***'''<span style="color:#ff0000">Low intensity (7): </span><span style="color:#0000ff">CHAPPSS</span>'''
***#'''<span style="color:#ff0000">Prostate </span><span style="color:#0000ff">C</span><span style="color:#ff0000">ancer</span>'''
***#*As 70% of all prostate cancers occur within the peripheral zone, the tissue characteristics allow for T2WI to detect a significant number of tumors in this zone
***#*
***#'''<span style="color:#0000ff">H</span><span style="color:#ff0000">emorrhage</span>'''
***#*Post-biopsy hemorrhage can interfere with tumor detection[https://pubmed.ncbi.nlm.nih.gov/26594835/], since areas of hemorrhage appear similar to cancer on T2WI
***#**If obtaining prostate MRI post-biopsy, a delay of 6-8 weeks after biopsy is recommended; but even with this delay, significant hemorrhage may be discovered, and, if present, the examination should be rescheduled[https://pubmed.ncbi.nlm.nih.gov/26594835/]
***#*Can be distinguished from cancer with T1WI (hemorrhage has high intensity on T1WI, cancer has low intensity on T2WI)
***#'''<span style="color:#0000ff">A</span><span style="color:#ff0000">trophy</span>'''
***#'''<span style="color:#0000ff">P</span><span style="color:#ff0000">rostatitis</span>'''
***#'''<span style="color:#0000ff">P</span><span style="color:#ff0000">ost-treatment changes</span>'''
***#'''<span style="color:#0000ff">S</span><span style="color:#ff0000">cars</span>'''
***#'''<span style="color:#0000ff">S</span><span style="color:#ff0000">tromal hyperplasia i.e. benign prostatic hyperplasia (BPH)</span>'''
***#*'''Clinical implication: On T2WI, BPH nodules can be difficult to distinguish from cancer'''
**Lesion shape
***Wedge-shaped/linear lesions are more likely benign 
* '''<span style="color:#ff0000">Diffusion weighted imaging (DWI)</span>'''
** '''Measures the diffusion of water protons within tissue'''
***'''In normal water-rich glandular tissue, protons are mobile'''
***'''In densely packed water-poor tissue such as that found in tumors, protons have restricted movement.'''
**Images are acquired by sequentially applying multiple magnetic field gradients, known as b-values, to calculate ADC values and construct ADC maps. 
***b-value is a factor that reflects the strength and timing of the gradients used to generate diffusion-weighted images. The higher the ''b''-value, the stronger the diffusion effects.
****Typical ''b''-values available on modern MRI scanners range from 0 to about 4000 s/mm²[https://mriquestions.com/what-is-the-b-value.html]
***ADC values are calculated by the software and displayed as a parametric map reflecting the degree of diffusion of water molecules through different tissues.
****Different b-values will produce different ADC maps
****In general, ADC values decrease when b-values increase above 1000 s/mm²[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4730971/]
**'''<span style="color:#ff0000">Primary use:</span>'''
***'''<span style="color:#ff0000">Optimal sequence to evaluate lesions in the peripheral zone[https://pubmed.ncbi.nlm.nih.gov/31392526/]</span>'''
**'''<span style="color:#ff0000">Signal intensity</span>'''
***'''<span style="color:#ff0000">ADC maps</span>'''
****'''Intermediate intensity'''
*****'''Normal glandular prostate tissue allows unrestricted free water movement'''
****'''<span style="color:#ff0000">Low intensity</span>'''
*****'''<span style="color:#ff0000">Prostate cancer</span>[https://pubmed.ncbi.nlm.nih.gov/23878284/]'''
******'''Appears as high signal intensity focus on high b-value images'''
*******Image with highest b-value (lowest ADC) likely to be most useful
******'''<span style="color:#ff0000">Tumors with the higher restriction (low ADC values) tend to be higher grade</span>'''
*'''<span style="color:#ff0000">T1WI</span>'''
** Captures the movement of protons in the z-axis
** '''<span style="color:#ff0000">Primary uses (2):</span>'''
**#'''<span style="color:#ff0000">Optimal sequence to identify areas of hemorrhage within the prostate</span>'''
**#'''Often used to look at normal anatomical details.'''
** '''<span style="color:#ff0000">Signal intensity</span>'''
***'''<span style="color:#ff0000">High intensity</span>'''
****'''<span style="color:#ff0000">Hemorrhage/blood has high signal intensity on T1</span>, against a homogenous low signal background.'''
****'''<span style="color:#ff0000">Fat</span>'''
***'''<span style="color:#ff0000">Low intensity'''
****'''<span style="color:#ff0000">Fluids (CSF, urine)</span>'''
****'''<span style="color:#ff0000">Prostate cancer'''
* '''<span style="color:#ff0000">Dynamic contrast enhancement (DCE)</span>'''
** A series of T1WI obtained before, during, and after the injection of intravenous gadolinium-based contrast media
**'''<span style="color:#ff0000">Primary use (1):</span>'''
***'''<span style="color:#ff0000">Measures the vascularity of prostate tissue</span>'''.
**** '''Focal early hyperenhancement is suggestive of a malignancy'''
*****Tumors have increased vascularity due to neo-angiogenesis and, therefore, take up the contrast agent more rapidly than normal tissue. Moreover, this contrast washes out of tumor regions quickly leading to a steep wash-in-wash-out enhancement curve.
*****There is considerable overlap of with benign conditions, such as benign prostatic hyperplasia and prostatitis.
******DCE MRI is most helpful when the T2W MRI and DWI are equivocal.
*******In these cases, strong early enhancement or rapid washout of contrast media from the lesion increases the suspicion that the lesion is a clinically significant malignancy. 
****Very useful in detecting sites of recurrent prostate cancer after prostatectomy or radiation therapy where focal enhancement may indicate a site of focal recurrence
* '''<span style="color:#ff0000">Magnetic resonance spectroscopic imaging (MRSI)</span>'''
** '''Uses the relative concentration of cellular metabolites in the prostate, specifically citrate and choline, to detect prostate cancer.'''
*** '''Citrate is a marker of normal prostatic tissue, whereas high levels of choline can be found in cancerous cells owing to increased cell turnover, which, in turn, leads to an increased choline-to-citrate ratio in patients with prostate cancer'''
** '''<span style="color:#ff0000">When combined with T2WI, MRSI has been found to have the highest sensitivity of all MRI sequences (92%) in detecting prostate cancer.</span>'''
** While MRSI is a promising imaging sequence, it requires an extra 10 to 15 minutes of examination time. Also, for this phase an endorectal coil (see below) is mandatory at 1.5T and optional at 3T. For these reasons, MRSI is less commonly performed than other mpMRI sequences in prostate MRI studies.
* '''Bi-parametric MRI (bpMRI)'''
** '''Combination of only non-contrast T2WI and DWI (with ADC maps) series''' 
**Advantages[https://pubmed.ncbi.nlm.nih.gov/26594835/]
***Can be performed without an endorectal coil
***Can be performed intravenous access and contrast administration
***Fewer sequences reduces time/costs to complete study
****Requires less than half the in-bore magnet time to perform compared with the complete mpMRI
**Disadvantages
***Fewer imaging sequences which may limit adequate interpretation
**'''No significant difference in sensitivity or specificity compared to mpMRI'''
***Systematic review and meta-analysis (2018)
****20 studies involving 2142 patients
****Results
*****No significant difference in pooled sensitivity and specificity
******Sensitivity: 0.74 (95% CI, 0.66–0.81) bpMRI vs. 0.76 (95% CI, 0.69–0.82) mpMRI
******Specificity: 0.90 (95% CI, 0.86–0.93) bpMRI vs. 0.89 (95% CI, 0.85–0.93) mpMRI
****[https://pubmed.ncbi.nlm.nih.gov/30240296/ Woo, Sungmin, et al.] "Head-to-head comparison between biparametric and multiparametric MRI for the diagnosis of prostate cancer: a systematic review and meta-analysis." ''American Journal of Roentgenology'' (2018): W226-W241.

====== <span style="color:#ff0000">Magnet strength</span> ======
* '''mpMRI can be performed at field strengths of 1.5T or 3T with or without an endorectal coil.'''
** 3T magnets reduce image acquisition time and improve spatial resolution
** Greater magnet strength does not necessarily mean greater cancer detection rates.

====== <span style="color:#ff0000">Endorectal coil</span> ======
* '''Advantages'''
**'''<span style="color:#ff0000">Improves image resolution by increasing the SNR</span>''' 
***'''Standard clinical field strengths of 1.5T do not provide sufficient signal-to-noise ratio for clinical diagnosis of prostate cancer. To compensate for this deficiency, the use of surface and/or endorectal coil arrays has been proposed'''
***'''There is consensus regarding the use of a surface body coil and an endorectal coil at 1.5T but controversy remains regarding the need for an endorectal coil at 3T.'''
**** '''<span style="color:#ff0000">The highest signal-to-noise ratio (SNR) is achieved at 3T with an endorectal coil</span> but acceptable results can be achieved at 3T without an endorectal coil.'''
*Disadvantages
**Patient discomfort
**Additional time required for proper placement and verification
**Cost
**Deformation of the gland which may affect the image registration for targeted biopsy or radiation planning
***Concerns regarding alterations in prostate volume have largely been dispelled.

====== <span style="color:#ff0000">Prostate Imaging and Reporting Archiving Data System (PI-RADS) ======
* '''Provides guidance for interpretation of different sequences and prostate zones'''
*Introduced in 2012, revised in 2015 (version 2.0)
*'''Each lesion is scored, using a 5-point scale based on the likelihood (probability) that mpMRI findings correlate with the presence of a clinically significant cancer'''
**Clinically significant cancer is defined on pathology/histology as (3):[https://pubmed.ncbi.nlm.nih.gov/26427566/]
**#Gleason score ≥7 (including 3+4 with prominent but not predominant Gleason 4 component) and/or 
**#Volume ≥0.5cc and/or 
**#Extra prostatic extension(EPE).
**'''Detection rates by PI-RADS score for any prostate cancer[https://pubmed.ncbi.nlm.nih.gov/37096582/]'''
*** '''PR 1-2: 15%'''
*** '''PR 3: 25%'''
*** '''PR 4: 58%'''
*** '''PR 5: 85%'''
**'''<span style="color:#ff0000">Positive predictive values for ISUP grade group ≥2 based on PI-RADS score:</span>[https://pubmed.ncbi.nlm.nih.gov/35393568/]'''
***'''<span style="color:#ff0000">PI-RADS 1-2: 7%[https://pubmed.ncbi.nlm.nih.gov/37096582/]</span>'''
***'''<span style="color:#ff0000">PI-RADS 3: 12–15%</span>'''
***'''<span style="color:#ff0000">PI-RADS 4: 39–48%</span>'''
***'''<span style="color:#ff0000">PI-RADS 5: 72%</span>'''
**If PIRADS[https://pubmed.ncbi.nlm.nih.gov/26427566/]
***≥4 or 5, biopsy should be considered
***≤3, biopsy may or may not be appropriate, depending on factors other than mpMRI alone
* Lesions in the peripheral zone appear round or irregular, and are focally hypointense, whereas transition zone lesions are non-circumscribed and moderately hypointense, and may exhibit a characteristic ‘‘erased charcoal’’ sign.

====== <span style="color:#ff0000">Test Characteristics ======

* '''<span style="color:#ff00ff">Cochrane Systematic Review and Meta-analysis (2019)</span>'''
** '''MRI compared with template‐guided biopsy'''
***'''Detection of grade 2 or higher prostate cancer'''
****'''Sensitivity: 0.91 (95% CI 0.83 to 0.95)'''
****'''Specificity: 0.37 (95% CI 0.29 to 0.46)'''
***'''Detection of grade 3 or higher prostate cancer'''
****'''Sensitivity: 0.95 (95% CI 0.87 to 0.99)'''
****'''Specificity: 0.35 (95% CI 0.26 to 0.46)'''
**[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483565/ Drost, Frank‐Jan H., et al.] "Prostate MRI, with or without MRI‐targeted biopsy, and systematic biopsy for detecting prostate cancer." ''Cochrane Database of Systematic Reviews'' 4 (2019).
*'''<span style="color:#ff00ff">PROMIS (2017)</span>'''
** '''<span style="color:#ff0000">Objective: evaluate sensitivity/specificity of prostate MRI vs. standard TRUS biopsy,</span> with template prostate mapping biopsy as gold standard reference'''
** Population: 576 men with a clinical suspicion of prostate cancer (elevated serum PSA (up to 15 ng/mL) within previous 3 months, suspicious digital rectal examination, suspected organ confined stage T2 or lower on rectal examination, or family history) and no previous prostate biopsy
** '''Intervention: prostate MRI followed by template prostate mapping biopsy as gold standard reference and then standard TRUS biopsy'''
***MRI was done with 1.5 Tesla magnet
***Patients with positive MRI did not undergo targeted biopsy
** Primary outcomes: sensitivity and specificity of prostate MRI vs. standard TRUS biopsy for detection of clinically significant prostate cancer
***Clinically significant prostate cancer defined as Gleason score ≥4 + 3 or a maximum cancer core length 6 mm or longer
**'''<span style="color:#ff0000">Results:</span>'''
*** '''<span style="color:#ff0000">mpMRI displayed a moderate sensitivity</span>''' (88%) and negative predictive value (76%), '''<span style="color:#ff0000">but poor specificity</span>''' (45%) and positive predictive value (65%).
**Authors' interpretation: MP-MRI, used as a triage test before first prostate biopsy, could reduce unnecessary biopsies by ≈25% (based on negative-predictive value). MP-MRI can also reduce over-diagnosis of clinically insignificant prostate cancer and improve detection of clinically significant cancer.
**[https://pubmed.ncbi.nlm.nih.gov/28110982/ Ahmed, Hashim U., et al.] "Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study." The Lancet 389.10071 (2017): 815-822.

====== <span style="color:#ff0000">Advantages</span> ======

* '''Compared to pathway of elevated PSA to TRUS-guided biopsy without MRI, pathway of elevated PSA to MRI with targeted biopsy''' 
** '''Improves identification of anterior tumors'''
** '''Reduces over diagnosis of clinically insignificant prostate cancer'''
** '''Increases diagnosis of clinically significant prostate cancer'''
*** '''≈10%''' (but up to 20%) '''of negative MRI have clinically significant prostate cancer'''
* '''<span style="color:#ff00ff">PRECISION (2018)</span>'''
** Objective: in males with clinical suspicious of prostate cancer, determine whether prostate MRI with targeted biopsy only can increase detection of clinically significant prostate cancer and decrease detection of clinically insignificant prostate cancer
** '''Design: Non-inferiority trial'''
** '''<span style="color:#ff0000">Population: 500 males with clinical suspicion of prostate cancer based on elevated PSA or abnormal DRE</span>'''
** '''<span style="color:#ff0000">Randomized to standard TRUS–guided biopsy vs. MRI +/- targeted biopsy</span>'''
*** '''Males in the MRI group underwent a targeted biopsy (without standard biopsy cores) if the MRI was suggestive of prostate cancer; if MRI results were not suggestive of prostate cancer, males were not offered biopsy'''
** '''Outcomes'''
*** '''Primary: proportion of males who received a diagnosis of clinically significant cancer'''
*** Secondary: proportion of males who received a diagnosis of clinically insignificant cancer
** '''<span style="color:#ff0000">Results:</span>'''
*** '''<span style="color:#ff0000">MRI-targeted biopsy was non-inferior and superior to detecting clinically significant cancer</span>''' (absolute risk difference 12%, 38% MRI vs. 26% standard TRUS)
*** '''<span style="color:#ff0000">MRI-targeted biopsy was associated with fever patients being diagnosed with clinically insignificant cancer</span>''' (absolute risk difference -13%)
** Authors’ conclusion: Using MP-MRI to triage men might allow 27% of patients avoid a primary biopsy and diagnosis of 5% fewer clinically insignificant cancers. If subsequent TRUS-biopsies were directed by MP-MRI findings, up to 18% more cases of clinically significant cancer might be detected compared with the standard pathway of TRUS-biopsy for all. MP-MRI, used as a triage test before first prostate biopsy, could reduce unnecessary biopsies by a quarter. MP-MRI can also reduce over-diagnosis of clinically insignificant prostate cancer and improve detection of clinically significant cancer.
** [https://pubmed.ncbi.nlm.nih.gov/29552975/ Kasivisvanathan, Veeru, et al.] "MRI-targeted or standard biopsy for prostate-cancer diagnosis." New England Journal of Medicine 378.19 (2018): 1767-1777.
* '''<span style="color:#ff00ff">STHLM3 - MRI-targeted vs. standard biopsy in prostate cancer screening</span>'''
**'''Population: 1532 males aged 50-74 years with screening PSA > 3 ng/mL'''
***Screening population in STHLM3, compared to patients referred for abnormal PSA or DRE in PRECISION
**'''Randomized to standard TRUS-guided biopsy vs. MRI and if MRI positive then standard biopsy with targeted biopsy'''
***If MRI negative, biopsies were not performed unless Stockholm3 test scores ≥25% or greater
** Primary outcome: proportion of males diagnosed with clinically significant cancer (Gleason score ≥7)
** Secondary outcome: proportion of males diagnosed with clinically insignificant cancers (Gleason score 6).
** Results
*** MRI non-inferior to diagnose clinically significant disease (21% MRI vs. 18% standard biopsy)
*** Significantly fewer clinically insignificant disease with MRI (4% MRI vs. 12% standard biopsy)
** [https://pubmed.ncbi.nlm.nih.gov/34237810/ Eklund, Martin, et al.] "MRI-targeted or standard biopsy in prostate cancer screening." ''New England Journal of Medicine'' (2021).

====== <span style="color:#ff0000">Disadvantages</span> ======

* '''Availability/cost'''
* '''Interobserver reproducibility remains a challenge.[https://pubmed.ncbi.nlm.nih.gov/32315265/]'''
* '''Learning curve related to reading MRI and to performing fusion biopsies'''
* '''Use of MRI for tumor staging remains controversial.'''
**Variable sensitivities (13-91%) and specificities (49-97%) have been reported for predicting extra-capsular extension.

====== Guidelines on Use of MRI Before Biopsy ======

* '''2023 AUA Guidelines on Early Detection of Prostate Cancer'''
**'''<span style="color:#ff0000">May be used prior to initial biopsy to increase the detection of GG2+ prostate cancer[https://pubmed.ncbi.nlm.nih.gov/23659877/]</span>'''
***It is reasonable to obtain an mpMRI in biopsy-naïve patients prior to their first biopsy, but such a practice cannot be regarded as the standard approach based on the currently available evidence. 
*'''2023 NCCN (PROSD-3)'''
**'''Multiparametric MRI is strongly recommended, if available'''
*'''2022 EAU[https://uroweb.org/guidelines/prostate-cancer/chapter/diagnostic-evaluation]'''
**'''Systematic biopsy is an acceptable approach in case MRI is unavailable''' 
*2017 Cancer Care Ontario Guidelines
** '''<span style="color:#ff0000">Biopsy-naïve: MRI should not be considered standard of care'''
** '''<span style="color:#ff0000">Prior negative biopsy: MRI followed by targeted biopsy may be considered</span>'''

====== Targeted biopsy only vs. targeted and systematic ======
* '''<span style="color:#ff00ff">MRI-FIRST (2019)</span>'''
** Objective: determine whether biopsy of MRI detected lesions increases detection of clinically significant prostate cancer compared to standard biopsy i.e. can we omit standard biopsy and do only targeted biopsy?
** '''Design: paired-diagnostic study (non-randomized)'''
**'''Population: 275 patients with clinical suspicion of prostate cancer'''
** '''Intervention: MRI followed by standard systematic biopsy then targeted biopsy of up to 2 lesions on MRI. Patients with negative multiparametric MRI (Likert score ≤2) had systematic biopsy only.'''
** '''Primary outcome: detection of clinically significant prostate cancer'''
** '''Results:'''
*** '''No difference in detection of clinically significant prostate cancer''' (30% systematic biopsy vs. 32% targeted biopsy)
*** Clinically significant prostate cancer would have been missed in 5% of patients had systematic biopsy not been done, and in 8% of patients had targeted biopsy not been done
** '''Obtaining a multiparametric MRI before biopsy in biopsy-naive patients can improve the detection of clinically significant prostate cancer compared to systematic biopsy alone but does not seem to avoid the need for systematic biopsy'''
** '''</span>'''[https://pubmed.ncbi.nlm.nih.gov/30470502/ Rouvière, Olivier, et al.] "Use of prostate systematic and targeted biopsy on the basis of multiparametric MRI in biopsy-naive patients (MRI-FIRST): a prospective, multicentre, paired diagnostic study." The Lancet Oncology 20.1 (2019): 100-109.
*'''<span style="color:#ff00ff">Ahdoot et al. (2020)</span>'''
**Study design: cohort study
**Population: 2103 males with an elevated PSA or abnormal DRE with a positive MRI underwent a targeted and systematic biopsy
**Outcomes:
***Primary outcomes: cancer detection rates by grade group for each biopsy method
**Results
***Use of MRI-targeted biopsy led to more diagnoses of cancers in grade groups 3, 4, and 5 than systematic biopsy and fewer cancers in grade group 1
***The addition of MRI-targeted biopsy to systematic biopsy led to 208 (9.9%) more prostate cancer diagnoses. Of these new diagnoses, 59 (28.4%) were clinically significant (grade group ≥3) disease.
***MRI-targeted biopsy was responsible for upgrading of events in 458 patients (21.8%) when added to systematic biopsy
***MRI-targeted biopsy alone without systematic biopsy would have led to no detection of cancers of grade group 2 or higher in 123 patients (5.8%) and no detection of cancers of grade group 3 or higher in 41 patients (1.9%)
***Among the patients who underwent radical prostatectomy, upgrading on histopathological analysis after undergoing combined biopsy occurred 14% of patients. The rates of any upgrading or clinically significant upgrading on whole-mount histopathological analysis were substantially higher for systematic biopsy and MRI-targeted biopsy (30.9% and 8.7%, respectively) than for combined biopsy
**Authors' interpretation: Among patients with MRI-visible lesions, combined biopsy led to more detection of all prostate cancers. However, MRI-targeted biopsy alone underestimated the histologic grade of some tumors. After radical prostatectomy, upgrades to grade group 3 or higher on histopathological analysis were substantially lower after combined biopsy.
**[https://pubmed.ncbi.nlm.nih.gov/32130814/ Ahdoot, Michael, et al.] "MRI-targeted, systematic, and combined biopsy for prostate cancer diagnosis." ''New England Journal of Medicine'' 382.10 (2020): 917-928.
*'''<span style="color:#ff00ff">GOTEBORG-2 (2022/2024)</span>'''
**Objective: Determine whether targeted-biopsy only (and avoid systematic) is adequate in patients with elevated PSA (3-10 ng/ml) and prostate MRI
**Population: Swedish males aged 50-60 living in Gothenburg, Sweden, without previous diagnosis of prostate cancer
**Randomized to invited screening with PSA test vs. no invitation
***If PSA > 3 ng/mL, patients underwent prostate MRI
****Further randomized to
*****Reference group: Systematic (regardless of MRI results) +/- targeted biopsy if MRI positive (PR3-5) vs.
*****Experimental group: Targeted biopsy only if MRI positive (PR3-5) (experimental group); If PSA>10, patients underwent systematic biopsy, with or without targeted biopsy, regardless of MRI results
******If low-grade prostate cancer (mainly with Gleason 3+3 cancer but also some with Gleason 3+4 cancer) detected by targeted biopsy in the experimental group, were invited to undergo follow-up systematic biopsy. The Gleason score was thus based on both targeted and systematic biopsies after a cancer diagnosis in both groups in order to avoid sampling bias due to different primary biopsy techniques. 
**Outcomes:
***Primary outcome: detection of clinically insignificant prostate cancer, defined as a Gleason score of 3+3.
***Secondary outcome: detection of clinically significant prostate cancer, defined as a Gleason score of 3+4 or higher
**Results:
***19,733 (52%) of those randomized to invitation to screening underwent PSA testing
****1371 (7%) had PSA > 3 ng/mL
*****95% of patients with PSA > 3 ng/mL underwent MRI
***Risk of clinically insignificant prostate cancer at screening or at interval: significantly more common in patients undergoing systematic +/- targeted biopsy compared to targeted biopsy only (2.4% vs. 1.0%)
***Risk of clinically significant prostate cancer at screening or at interval: no significant difference (2.1% systematic +/- targeted vs. 1.8% targeted biopsy only)
***(2022 publication) 10 patients in reference group found to have clinically significant prostate cancer on systematic only
****9 with negative MRI, 1 with false-positive MRI
*****All GG2, GG4 <5% in 6 patients
******6 managed with AS
***(2022 publication) 128 patients in experimental group with PSA <10 diagnosed with cancer by targeted biopsy only
****72/128 (56%) had GG1
*****86% underwent systematic biopsy
*****26% upgraded (all GG2 except 1 to 3+5)
****Gleason 3+3 lesions that had been detected by systematic biopsy differed only in tumor extension from those that had been detected by targeted biopsy of suspicious lesions shown on MRI, with greater volume measured in tumors that were visible on MRI
**Author's interpretation: omitting prostate biopsy in men with negative MRI results, and thereby delaying a potential cancer diagnosis, was associated with a substantial reduction in the detection of clinically insignificant cancer and a very low risk of detecting incurable cancers at repeat screening rounds or as interval cancers.
**[https://pubmed.ncbi.nlm.nih.gov/39321360/ Hugosson, Jonas, et al.] "Results after Four Years of Screening for Prostate Cancer with PSA and MRI." ''New England Journal of Medicine'' 391.12 (2024): 1083-1095.
**[https://pubmed.ncbi.nlm.nih.gov/36477032/ Hugosson, Jonas, et al.] "Prostate cancer screening with PSA and MRI followed by targeted biopsy only." ''New England Journal of Medicine'' 387.23 (2022): 2126-2137.

====== Biopsy after Negative MRI ======

* '''≈10%''' (but up to 20%) '''of negative MRI have clinically significant prostate cancer'''
* '''Predictors of clinically significant prostate cancer in presence of negative MRI[https://pubmed.ncbi.nlm.nih.gov/31967522/]'''
** PSA density > 0.15 ng/ml/cc[https://pubmed.ncbi.nlm.nih.gov/30189186/][https://pubmed.ncbi.nlm.nih.gov/33080153/]
** History of previous negative biopsy[https://pubmed.ncbi.nlm.nih.gov/30189186/]
** Abnormal DRE[https://pubmed.ncbi.nlm.nih.gov/33080153/]/Clinical stage T2a or greater[https://pubmed.ncbi.nlm.nih.gov/33080153/]
** Prostate cancer family history[https://pubmed.ncbi.nlm.nih.gov/33080153/]