FIGURE 1. INTRODUCTION: The following schemes are the 2015 updated synopsis derived from the updated ITALIAN PROSTATE BIOPSIES GROUP’S GUIDELINES, rated through the GRADE SYSTEM. They have been designed to guide the Physicians through the prostate biopsy/re-biopsy “decision making” process and to aid them during the same procedure. HOW TO READ THE GUIDELINES’ COMPENDIUM: For each “Critical Hotpoint” the weight of every factor to consider will be represented by three different arrows:

ADVISABLE: All the FACTORS/ACTIONS we suggest to evaluate and/or carry out

OPTIONAL: All the FACTORS/ACTIONS we consider optional to evaluate and/or carry out

MODULATING FACTORS: Aspects that might influence the FACTORS/ACTIONS during the clinical practice

Comorbidities Fragilities

Quality of Life Improvements

FIGURE 2. 1st BIOPSY

1. INDICATION TO 1st BIOPSY

* Multiparametric MRI (mpMRI) not recommended in biopsy naïve patients

Prostate Nomograms Free PSA /total PSA < 10%

Prostate Health Index PHI® > 40 PCA3 Score > 35

PSA Velocity > 0.7 ng/ml/yr PSA Density > 0.20

PSA Doubling time < 3yr Positive mpMRI* PIRADS 3

TRUS + Familiar History +

High Risk Populations Pre-BPH Surgery

Any PSA raise from Nadir in 5ARI intake

Digital Rectal Exam (DRE) +

Confirmed Total PSA value > 10 ng/mL

Positive mpMRI* PIRADS 4

1st

B I O P S Y

PSA < 10 ng/mL PSA > 10 ng/mL REPEAT DOSAGE TO CONFIRM VALUE

(if reasonable, subsequent to medical therapy)

FIGURE 3. 1st BIOPSY

2. TRUS-GUIDED BIOPSY TECHNIQUES

TRANSRECTAL TRANSPERINEAL 1st

B I O P S Y

FIGURE 4. 1st BIOPSY

3. NUMBER OF SAMPLED CORES

SAMPLED CORES ≥ 12

PROSTATE VOLUME

AGE >75yr COMORBIDITIES FRAGILITIES

TARGETED CORES: Positive DRE Suspicious Imaging Areas

FIGURE 5. 1st BIOPSY

4. SAMPLED AREAS

* In candidates for BPH Surgery (i.e., laser vaporization)

PERIPHERAL ZONE

ANTERIOR ZONE* SUSPECT AREAS FROM

DRE/TRUS/MRI

1st

B I O P S Y

Comorbidities Fragilities

Quality of Life Improvements

FIGURE 6. RE-BIOPSY

1. INDICATION

Inadequate First Biopsy Set

ASAP Finding

Positive mpMRI PIRADS 4

PSA rising above 10 ng/mL

Active Surveillance Program

DRE Finding modifications

Adverse PSA Kinetics values

Persisted Elevated total PSA

Free PSA / total PSA < 10%

Prostate Health Index (PHI®)

Positive mpMRI PIRADS =3 PCA3 Score > 35

Multifocal HGPIN (> 3 cores)

TRUS +

PSA Density > 0.20

R E B I O P S Y

FIGURE 7. RE-BIOPSY

2. NUMBER OF SAMPLED CORES

3. SAMPLED AREAS

R E B I O P S Y

>12 CORES Anterior zone

included

SATURATION BIOPSY ( > 20 CORES)

MRI-GUIDED BIOPSY (Fusion/In-Bore/cognitive)

SUSPICIOUS TRUS AREA (Targeted Biopsy)

A R E A S

PERIPHERAL ZONE + ANTERIOR ZONE

TARGETED AREAS FROM SUSPICIOUS DRE/TRUS/MRI

(Fusion/In-Bore/cognitive)

FIGURE 8. RE-BIOPSY

4. REBIOPSY TIMING

5. BIOPSY TECHNIQUE

TRANSRECTAL BIOPSY

TRANSPERINEAL BIOPSY

MRI-GUIDED BIOPSY (Fusion/In-Bore/cognitive)

TEMPLATE BIOPSY (Transperineal)

R E B I O P S Y

R E B I O P S Y

NOT BEFORE 3 MONTHS

If negative DRE and/or imaging not strongly suspicious (i.e. PIRADS < 3):

BIOPSY REPEATED UP TO 3 TIMES

(Except for Patients in AS programs)

B I O P S Y

FIGURE 9. PROSTATE BIOPSY: PREPARATION

* Based on patient-adjusted risk **Except for patients contraindications or choice

Viral Markers

Coagulation screening panel

Urine culture

Antibiotic Therapy ≥ 3 Days

Ansiolitic and/or Analgesic administration

General Anesthesia

Providing informed consent

Co-medication History

Anticoagulant or Antiaggregant withdrawal*

(excluding ASA < 100mg/die)

Switching from Antiacoagulant to LMWH*

Antibiotic Prophylaxis

Endocarditis Prophylaxis (where required)

Cleansing Enema

Local Anesthesia** (infiltration +/- anesthetic jelly)

FIGURE 10. PROSTATE BIOPSY: REQUIRED MATERIALS

B I O P S Y

BIOPTIC GUN

TRANSRECTAL Ultrasound probe

16 / 18 Gauge Core Biopsy Needles

Disposable Automatic Core Biopsy Needles

FIGURE 11. Strategies for TRUS-guided prostate biopsy in order to prevent sepsis episodes

Risk Factors

Recurrent Bacterial Prostatitis At least 3 previous antibiotics intake within the last 6

months Previous several TRUS-guided prostate biopsies Active surveillance Recent hospital admission (within last 3 months) Inflammatory chronic bowel disease Immunodeficiency conditions

Stool culture (+ Antiobiogram)

Switching to transperineal biopsy

Urine culture (+ Antibiogram)

Double Antibiotic intake (p.o. Antibiotic + aminoglycosides)

Antibacterical enema

FIGURE 12. Multiparametric prostate MRI, indications, contraindications, technical requirements and reporting system

1. CLINICAL INDICATIONS FIRST BIOPSY: not indicated PREVIOUS NEGATIVE BIOPSY: clinical suspicion of PCa DETECTION mpMRI and

then TRUS or MRI GUIDED BIOPSY (Fusion/In-Bore/cognitive) POSITIVE BIOPSY FOR PCa

ACTIVE SURVEILLANCE: Staging mpMRI to confirm grade and etent CURATIVE INTENT: Staging mpMRI with bone and node in high risk

( From: Barentsz et al. ESUR prostate MR guidelines 2012. Eur Radiol 2012; 22: 746-757)

2. CONTRAINDICATIONS General contraindications to perform an MRI exam (obesity, claustrophobia, pace-makers etc.)

3. LIMITATIONS Possible limitations in case of hip prosthesis

m p

M R I

FIGURE 13. TECHINICAL REQUIREMENTS Barentsz et al. ESUR prostate MR guidelines 2012. Eur Radiol 2012; 22: 746-757 ESUR guidelines. Prostate MRI. http://www.esur.org/esur-guidelines/prostate-mri/

4-6 weeks after biopsy

Scanner 3T with or without endorectal coil Scanner 1.5T with endorectal coil or

≥16-channel pelvic phased array

High resolution T2 weighted sequences

DWI weighted sequence with high b-value (≥1000 s/mm2) and ADC map calculation

DCE-MRI (temporal resolution ≤15s; acquisition for 5 minutes to detect washout;

unenhanced images to detect post-biopsy haematomas

Axial T1 weighted sequences of pelvis for

nodes and bones evaluation

Antiperistaltic drugs (buscopan®, glucagon®)

MRSI

DWI:Diffusionweightedimaging DCE-MRI:Dynamiccontrast-enhancedmagneticresonanceimaging MRSI:Magneticresonancespectroscopicimaging

FIGURE 14. REPORTING SYSTEM

Barentsz et al. ESUR prostate MR guidelines 2012. Eur Radiol 2012; 22: 746-757 ESUR guidelines. Prostate MRI. http://www.esur.org/esur-guidelines/prostate-mri/

Detection and measurement of all prostatic abnormal lesions, with the identification of the index lesion

Localisation scheme

PI-RADS v2 score

Probability of extra-prostatic disease (EPE/SVI)

Incidental findings

EPE:extraprostaticextension SVI:seminalvesiclesinvasion

FIGURE 15. LOCALISATION SCHEME PI‐RADS v2 employs thirty‐nine regions: thirty‐six for the prostate, two for the seminal vesicles and one for the external urethral sphincter. Each lobe (right/left) is diveded in the following regions

APEX

PERIPHERAL ZONE (PZ)

anterior (a) / lateral posterior (pl) / medial posterior (mp)

TRANSITION ZONE (TZ) anterior (a) / posterior (p)

ANTERIOR FIBROMUSCOLAR STROMA (AS)

MIDGLAND PERIPHERAL ZONE (PZ)

anterior (a) / lateral posterior (pl) / medial posterior (mp)

TRANSITION ZONE anterior (a) / posterior (p) ANTERIOR FIBROMUSCOLAR STROMA (AS)

BASE

PERIPHERAL ZONE (PZ)

anterior (a) / lateral posterior (pl)

TRANSITION ZONE (TZ)

anterior (a) / posterior (p)

CENTRAL ZONE (CZ) ANTERIOR FIBROMUSCOLAR STROMA (AS)

SEMINAL VESCICLES EXTERNAL URETHRAL SPHINCTER

(from: ESUR guidelines. Prostate MRI. http://www.esur.org/esur-guidelines/prostate-mri/)

FIGURE 16. PI-RADS v2 SCORE

ESUR guidelines. Prostate MRI. http://www.esur.org/esur-guidelines/prostate-mri/

FIGURE 17. PROSTATE BIOPSY: PREPARATION OF THE SAMPLED SPECIMENS

SAMPLED CORES LENGTH > 10 mm

SEPARATION AND IDENTIFICATION OF

EACH CORE

FORMALDEHYDE FIXATION

EACH SPECIMEN INCLUDED IN A

SINGLE PLASTIC CAGE

SPECIMEN INKING FOR ITS CORRECT

ORIENTATION

SPECIMEN TO

PATHOLOGIST

B I O P S Y

R E P O R T

C L I N I C A L

C L I N I C A L

H I S T O L O G I C A L

H I S T O L O G I C A L

FIGURE 18. PROSTATE BIOPSY: REPORT PREPARATION

Eventual early and late adverse events

Eventual Pharmacological Therapy

Informative Paper (Possible Comorbidities and Side

Effects) Personal records and

clinical data

Number of Positive Cores / Number of Total Cores

Length of Each sampled cores % of Prostate cancer for each

positive core GS Grading for each positive core

(ISUP 2014) % of Gleason Pattern 4

(in GS 3+4 or 4+3) ASAP findings

HGPIN findings Perineural Invasion

Extracapsular Invasion Intraductal Spreading

Presence of Atrofic / Inflammatory findings Explanation for ASAP

classifying Length of Cancer for each

positive core

Immunohistochemical Staining

Seriated Biopsy Evaluation of more Layers of

Biopsy Presence of Neuroendocrine

Differentiation

FIGURE 19. PROSTATE BIOPSY: HISTOLOGICAL REVISION

HISTOLOGY FROM

ANOTHER HOSPITAL FACILITY

ASAP AND/OR FROM ANOTHER HOSPITAL

FACILITY

> 3 CORES WITH MULTIFOCAL HGPIN

PREVIOUS ASAP

PATIENT INCLUDED IN AN ACTIVE

SURVEILLANCE PROGRAM

HISTOLOGICAL REVISION

ANY CASE WHERE HYSTOLOGY MIGHT

CHANGE THERAPEUTIC STRATEGIES

APPENDIX 1: Histological definition of GLEASON GRADE, based on ISUP 2014, and PROGNOSTIC GROUPS, based on WHO 2016

1. INNOVATIONS FROM 2014 ISUP CONSENSUS CONFERENCE

Gleason pattern 3 is limited to discrete glands, either simple or branched, well-formed and divisible from each others Presence of cribriform glands or groups of poorly-formed glands is included in Gleason pattern 4 Occasional/seemingly poorly formed or fused glands between well-formed glands is insufficient for a diagnosis of pattern 4 Glomeruloid glands should be assigned a Gleason pattern 4, regardless of morphology In cases with borderline morphology between Gleason pattern 3 and pattern 4 and crush artifacts, the lower grade should be favored Grading of mucinous carcinoma of the prostate should be based on its underlying growth pattern despite from mucinous presence Gleason Pattern 4 is attributed to ductal carcinoma Small solid cylinders, solid medium to large nests with rosette-like spaces, presence of comedonecrosis, even if focal, should be unequivocal

considered to represent Gleason pattern 5 Gleason Grade should not be assigned to small cell carcinoma Introduction of intraductal carcinoma with presence of large acini and prostatic ducts, preservation of basal cell, solid or dense cribriform

pattern, or loose cribriform or micropapillary pattern plus either nuclear atypia or necrosis. If intraductal carcinoma is found, even without invasive carcinoma, Gleason Grade should not be assigned and a comment either to its invariable association with aggressive prostate cancer end the need of a radical treatment, should be made.

Percentage of Gleason Grade 4 is only limited to Gleason Score 3+4 or 4+3 References:

Epstein JI, Egevad L, Amin MB, Delahunt B, Srigley JR, Humphrey PA; and the Grading Committee. 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. 2015 Oct 21

World Health Organization for the 2016 edition of pathology and Genetics: Tumours of the Urinary System and Male Genital Organs.

APPENDIX 2. HYSTOLOGICAL DEFINITIONS OF NEW PROGNOSTIC GRADE GROUPS BASED ON WHO 2016

GRADE GROUP 1 (Gleason Score 6): only individual discrete well-formed glands and divisible from each others GRADE GROUP 2 (Gleason Score 3+4 = 7): predominantly well-formed glands with lesser component of poorly- formed/fused/cribriform glands GRADE GROUP 3 (Gleason Score 4+3 = 7): predominantly poorly- formed/fused/cribriform glands with lesser component of well-formed glands GRADE GROUP 4 (Gleason Score 4+4 = 8; 3+5 = 8; 5+3 = 8): only poorly- formed/fused/cribriform glands GRADE GROUP 5 (Gleason Score 9-10): lacks gland formation (or with necrosis) with or without poorly- formed/fused/cribriform glands

The new system based on the GRADE GROUP should be used in the immediate future simultaneously with the Gleason Score. References:

Epstein JI, Egevad L, Amin MB, Delahunt B, Srigley JR, Humphrey PA; and the Grading Committee. 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. 2015 Oct 21

World Health Organization for the 2016 edition of pathology and Genetics: Tumours of the Urinary System and Male Genital Organs.

APPENDIX 3. HISTOLOGICAL EXAMPLES

APPENDIX 4. EXAMPLE OF A CORRECT HYSTOLOGICAL PROSTATE BIOPSY REPORT

EXAMPLE OF A CORRECT HYSTOLOGICAL PROSTATE BIOPSY REPORT USING BOTH GLEASON SCORE (ISUP 2014) AND PROGNOSTIC GRADE GROUPS 1. Right apex Prostate Cancer Gleason Score 3+3=6 (ISUP 2014); Grade Group 1 (WHO 2016) 10% of biopsy core; tumoral extension 1 mm 2. Lateral right midgland Benign prostate tissue 3. Right base Prostate Cancer Gleason Score Gleason score 4+3=7 (ISUP 2014); Grade Group 3 (WHO 2016) 30% of biopsy core; tumoral extension 5 mm; Gleason Grade 4 70%. 4……. 5……. Comment Singles Gleason Score can be grouped in different Prognostic Grade Groups, from 1 (less aggressive) to 5 (most aggressive), (Eur Urol. 2015 Jul 9. BJU Int. 2013; 111:753-60)