Advances in MR Imaging of PROSTATE CANCER Demetri Papadatos, MD, FRCPC Abdominal Imaging Radiologist Director, Abdominal Imaging Fellowship Director, Percutaneous Radiofrequency Ablation The Ottawa Hospital

PROSTATE CANCER Most common malignancy of men in US after skin cancer At autopsy, prostate cancer is found in 30% of men at age 50 almost 90% at age 90 About one in six men will be diagnosed with prostate cancer during lifetime However, only 1 / 34 will die of the disease

PROSTATE CANCER Many cancers are indolent, show no signs of clinical growth Despite the long latent period, second commonest cause of cancer death in American men over age 55

ETIOLOGY - RISK FACTORS All men are at a risk of developing prostate cancer. Age : Greatest risk factor risk increasing significantly after 50 yrs Family history: Men with affected father or brother at increased risk ACA Recommendation to start screening 10 yrs earlier compare to general population Genetic Factors – abnormal genes in 10 % but genetic testing is not available yet Race: more frequent and aggressive in African American men Environmental and dietary factors

HISTOPATHOLOGICAL TYPES More than 95% of prostatic malignancies are adenocarcinomas Rarely, a squamous or transitional cell neoplasm Very rarely sarcoma

Routine Screening is offered Men > 50 yrs With a life expectancy of at least 10 yrs Screening consists of : Digital rectal examination Serum PSA levels

PSA (Prostatic Specific Antigen) Secreted into blood stream by the prostate gland It’s routine use for screening has lead an exponential rise in prostate cancers, which are being detected much earlier Elevated PSA = non specific Also seen in benign prostatic hypertrophy (BPH) and prostatitis (benign conditions)

If PSA elevated Repeat PSA level a few weeks later when probable occult prostatitis has resolved Calculate PSA Density (PSA/gland volume) increases PSA specificity transrectal ultrasound (TRUS) = gland volume + ? Nodules Free PSA increases PSA specificity Low in CA Elevated in benign prostatic hypertrophy (BPH) If < 25 % of PSA is free – worrisome for cancer

DIAGNOSIS Diagnosis of prostate carcinoma is usually made by TRUS-guided core biopsy. However, can have +ve/rising PSA but –ve biopsies Dilemma Do these patients have prostate cancer ??? If so, why are the biopsies negative ???

Transrectal Ultrasound (TRUS) and Biopsy (Bx) TRUS can assess gland volume (PSAD) and detect nodules However, nodules may or may not represent cancer Therefore, perform multiple biopsies in attempt to find the suspected cancer TRUS is used to guide needle placement for biopsies

TRUS Bx Systematic approach needed during biopsy session in order to maximize the yield Number and location of biopsies varies Trend is to increase the number of biopsies obtained Some cancers are located in nodules seen on TRUS However, more aggressive cancer may be located elsewhere and not visible on TRUS Malignant prostatic nodules tend to look hypoechoic (dark) and demostrate increased vascularity

EXTENDED BIOPSY PROTOCOLS Traditionally, a six biopsy protocol was used Insufficient, tumours being missed and undergraded In particular, midline and apicolateral PZ tumours were missed 8 -10 biopsies improve diagnostic yield by 20–30% over traditional number of biopsies Some centers recommend 24 biopsies (12 per side) to get +ve diagnosis to accurately grade the tumor

PATHOLOGY Gleason GRADE and Gleason Score Gleason Grade  1=Low …….. 5=High

GLEASON SCORE A grade is assigned to the 2 largest foci of cancer These 2 grades are added together to yield the Gleason score (eg. Grade 3 + Grade 4 = Score of 7) Gleason Score varies between 2 and 10 The higher the Gleason score – more aggressive tumor NB: Score of 7 (3+4 vs 4+3)

GLEASON SCORE 2-6 = Low Risk 7 = Intermediate risk 8-10 = High risk

My prostate biopsy was positive, now what ? Surgery only proven curative treatment Only tumor confined to prostate is curable Surgery = HIGH morbidity/complications urinary incontinence + sexual impotence Need reliable staging tool to predict who will benefit from surgery Before the advent of accurate staging with imaging, nomograms were developed

CLINICAL NOMOGRAMS Originally designed to help predict the STAGE (as determined after surgery) and best course of treatment. "Partin tables" originally developed by 2 urologists (Alan W. Partin and Patrick C. Walsh) based on accumulated data from hundreds of patients treated for prostate cancer Most recent version of the Partin Tables, released in 2001 based on data from 5000 patients underwent radical prostatectomy at Johns Hopkins Can be used to determine pre test probabability of unresectable disease and decide if surgery is worth the potential complications

ROLE OF MRI MR can detect cancer but is not recommended as an initial screening tool (PSA, DRE, TRUS Bx) However  ? +ve PSA but –ve biopsy Does this patient have cancer ??? MR helps target repeat biopsy to suspicious areas Local Staging (to determine best treatment)

( ie significant chance of tumor progression) WHO NEEDS MRI STAGING Most patients with prostate CA have indolent cancer Will unlikely need any form of treatment during their lives as cancer will never manifest clinically High (+/- intermediate) risk groups ( ie significant chance of tumor progression)

WHO NEEDS MRI STAGING Staging MR would be cost effective if performed ONLY in the subgroup of patients with Palpable tumor PSA > 10 At least 50 % positive cores for malignancy High Gleason grade and score

IMAGING THE PROSTATE GLAND Currently imaging at 1.5 Tesla scanner is recommended Endorectal /Surface Coil MRI combination is best for anatomic detail High SNR High spatial resolution of 0.5 mm 5 MR techniques will be discussed today T2 Weighted Imaging Dynamic contrast enhanced MRI (DCE-MRI) MR Spectroscopic Imaging (MRSI) Diffusion weighted Imaging (DWI) Lymphotropic Nanoparticle-enhanced MRI (Ferumoxtran-10)

NORMAL ANATOMY

ANATOMY OF THE GLAND Glandular (acinar) and nonglandular elements I - Glandular prostate 1- Outer components Central zone (CZ) Peripheral zones (PZ) 2- Inner components Periuretheral glands Transitinal zone (TZ) (BPH) II - Nonglandular portions Prostatic urethra Anterior fibromuscular band

ABNORMAL GLAND

DISTRIBUTION OF PROSTATE CANCER Tumor location: 70 % in Peripheral Zone, PZ 20 % in Transition Zone, TZ 10 % in Central Zone, CZ Central gland most difficult to localize cancer because of overlapping signal intensity with normal gland / hypertrophy

LOCAL STAGING - IMPORTANCE Accurate tumor staging is essential to determine appropriate treatment (ie is curative surgery an option ?) Extracapsular Extension (ECE) Seminal Vesicle Invasion (SVI) Bladder/Rectal Invasion Lymph Node Metastases Only carcinomas confined within the prostate gland, are potentially curable by radical prostatectomy Staging usually classified using TNM classification

TNM CLASSIFICATION Primary tumor (T) TX: Primary tumor cannot be assessed T0: No evidence of primary tumor T1: Clinically inapparent tumor not palpable nor visible by imaging T1a: Tumor incidental histologic finding in <5% of tissue resected T1b: Tumor incidental histologic finding in >5% of tissue resected T1c: Tumor identified by needle biopsy (eg, because of elevated PSA) T2: Tumor confined within prostate T2a: Tumor involves < 50% of 1 lobe T2b: Tumor involves > 50% of 1 lobe T2c: Tumor involves both lobes T3: Tumor extends through the prostate capsule T3a: Extracapsular extension (unilateral or bilateral) ECE T3b: Tumor invades seminal vesicle(s) SVI T4: Tumor is fixed or invades adjacent structures other than seminal vesicles: bladder neck, external sphincter, rectum, levator muscles, and/or pelvic wall

TNM CLASSIFICATION Regional lymph nodes (N) Regional lymph nodes are the nodes of the true pelvis Distant lymph nodes are outside the true pelvis NX: Regional lymph nodes were not assessed N0: No regional lymph node metastasis N1: Single regional lymph node (inside the pelvis) < 2 cm N2: One or more regional lymph nodes, largest > 2 cm but < 5 cm N3: One or more regional lymph nodes, largest > 5 cm Distant metastasis (M) MX: Distant metastasis cannot be assessed (not evaluated by any modality) M0: No distant metastasis M1: Distant metastasis M1a: Non-Regional lymph node(s) M1b: Bone(s) M1c: Other site(s) with or without bone disease

STAGING OBJECTIVES To confirm organ-confined disease radical surgical prostatectomy could be offered without adjuvant radiation therapy. If disease is largely organ-confined with small volume periprostatic or seminal vesicle spread, radical radiotherapy can still be offered with / without pelvic nodal irradiation or with / without adjuvant hormonal therapy To confirm clinically suspected apical tumor or extent of LN metastases which will affect radiotherapy margins.

TIMING FOR MRI MRI should be delayed at least 4-8 weeks after biopsy Post biopsy hemorrhage may hamper tumor detection in the gland May result in under or overestimation of tumor presence and local extent MR “exclusion sign”: cancers are resistant to the development of post biopsy hemorrhage

LOCAL STAGING T STAGING

LOCAL STAGING Tumor extent Extra capsular extension Seminal vesicle invasion Volume of tumor Aggressiveness

ORGAN CONFINED DISEASE Primary tumor – TNM Stage of T2 or less Suitable for radical surgery Nerve sparing radical surgery if neurovascular bundles are clear Clinical estimation of the organ confined disease is based on clinical nomograms which takes into account PSA DRE Gleason score MR imaging has been shown to have an incremental value additive to clinical nomograms

MRI SIGNS OF UNRESECTABLE DISEASE ( TNM Stage > T2 ) Extra capsular extension - ECE Invasion of periprostatic fat Invasion of neuromuscular bundle Seminal Vesicle Invasion - (SVI) Invasion of adjacent organs (Bladder, Rectum) Metastases to pelvic lymph nodes

EXTRACAPSULAR EXTENSION - ECE

ECE Most imp to diagnose Endorectal coil imaging with T1 & T2W seq. only OR Endorectal imaging with spectroscopy

MRI SIGNS OF ECE Assessed on AXIAL & CORONAL images Contour deformity with step off or angulated margin Irregular bulge or capsule retraction Capsular breach & direct tumor extension Obliteration of rectoprostatic angle Asymmetry of neurovascular bundles

SEMINAL VESICLE INVASION

MRI SIGNS OF SEMINAL VESICLE INVASION (SVI) Combined AXIAL, SAGITAL & CORONAL images facilitates detection of SV invasion Contiguous low SI from base of gland in SV Extension of soft tissue along ejaculatory ducts Asymmetric decrease in SI of SV Decreased conspicuity of SV wall on T2WI

BLADDER & RECTAL INVASION

T2WI – SENITIVITY AND SPECIFICITY Varies widely for cancer detection Without endorectal coil Sensitivity : 45 % Specificity : 73 % With Endorectal coil Sensitivity : 77 - 91 % Specificity : 27 - 61 %

How do we increase specificity ? Keep Endorectal Coil MRI T2 imaging (high sensitivity) and add: Contrast-enhanced MRI (CE-MRI) MR Spectroscopic Imaging (MRSI) Diffusion-weighted MRI (DWI)

DYNAMIC CONTRAST ENHANCED MRI – DCE MRI

WHY TUMORS ENHANCE DIFFERENTLY THAN NORMAL TISSUES Cancers results in tumor angiogenesis Increased no. of vessels Increased permeability of vessels Increased interstitial tissue space

DCE MRI Fast GRE seq. can scan entire vol. of gland in few seconds Various perfusion parameters are electronically extracted according to time seq. Relative peak enhancement is most reliable perfusion parameter for cancer detection Improves specificity compared to T2W scans Tumors can be detected with higher accuracy but it does not improve staging

DCE MRI - IMPROVEMENT IN DETECTION RATES Peripheral zone cancers Sensitivity : 96 % Specificity: 97 % Compared to 75 % and 53 % respectively on T2WI Not tested in multi institutional trials Suffers from lack of uniformly accepted analytic method Still of unproven benefit as per ACR guidelines

DCE MRI – Analysis of data 3 methods of analysis Qualitative  Easier Look at curves Semi-Qualitative  Average Parameters from curves Quantitative  Complicated Mathematical Modelling

MR SPECTROSCOPY - MRS

SPECTROSCOPY – NORMAL SPECTRAL ANALYSIS 3D proton MR spectroscopic metabolic mapping of the entire gland is possible with a resolution of 0.24 ml per voxel. Proton MR spectroscopy displays concentrations of citrate, creatine, and choline metabolites found in the prostate gland and cancer. Normal prostate tissue contains high levels of citrate -higher in the PZ than in the central gland.

SPECTROSCOPY – SPECTRAL ANALYSIS Healthy peripheral-zone voxels typically have diagnostic levels of Cit with (Cho + Cr)/Cit ratios less than 0.5 Because of the proximity of the choline and creatine peaks at 1.5-T MR unit two peaks cannot be separated

TUMOR VOLUME

TUMOR VOLUME There is an association between primary tumor volume and local extent of disease, progression, and survival A review of a large number of prostate cancers in surgical and autopsy specimens showed Capsular penetration Seminal vesicle invasion and Lymph node metastases usually found only with tumors larger than 1.4 cc

TUMOR VOLUME Another study - ECE in 18 % with vol. < 3 cc 79% with volume > 3 cc Tumor volume – significant predictor of ECE Bx, TRUS and T2-MRI disappointing in volume estimation MRS provides more accurate volume estimation

ROLE OF SPECTROSCOPY IN ESTIMATING TUMOR VOLUME Relative tumor volume is determined on MRS ( counting the voxels containing abnormal spectra ) Improves Dx of ECE for both experienced and less experienced reader Decrease inter observer variability – further studies required to assure improvement in the performance of truly inexperienced reader

MR SPECTROSCOPY - MRS Technically demanding and time consuming Improvement in diagnostic accuracy and staging have been reported but not proved in multi institutional trials ACR clinical trial is currently underway Currently cannot be considered as routine diagnostic tool

Diffusion-weighted Imaging (DWI) Diffusion is the process of thermally induced random molecular displacement – Brownian motion Diffusion properties of tissues are related Amount of tissue water Tissue permeability Cancer tends to have restricted diffusion due to High cell densities Abundant intracellular membranes

DWI ADVANTAGES Short acquisition time High contrast resolution between tumor and normal tissue No need for endorectal Coil DISADVANTAGES Poor spatial resolution Potential risk of image distortion by post biopsy Hg

LOCAL STAGING N STAGING

ABNORMAL NODES Early metastases can occur in small nodes Size and shape of nodes inaccurate for staging ABNORMAL NODES Rounded configuration Short axis > 10 mm if oval, > 8 mm if round T1 OR T2 SI – not helpful Enhancement suggestive of metastatic lymph node

SHORTCOMINGS- NODAL STAGING Normal sized nodes - contain cancer as micro metastases Enlarged nodes may be reactive

DETECTION OF ABNORMAL LYMPH NODES Neither CT nor MRI is accurate as laparoscopic nodal dissection Initial step prior to radical prostatectomy remains nodal dissection MR is at least as accurate as CT in nodal staging If good chance the prostate cancer has already spread to the lymph nodes laparoscopic lymph node dissection is a minimally invasive procedure to begin with

Lymphotropic Nanoparticles ULTRASMALL SUPER PARAMAGNETIC MR contrast agents taken up by macrophages Distributes to LNs throughout the body Injected intravenously and imaged 24 hrs later +++ susceptibility effect on T2* MR images Cannot enter tumor (no macrophages) Can differentiate normal/reactive lymph nodes from malignant ones Iron based contrast agents not approved by FDA (Ferumoxtran-10)

Future trends 3T MRI Increased SNR Increased spatial resolution ? Assessment of microscopic disease ? Need for Endorectoil Coil Standardized technique for CE-MRI with availability of vendor software Approval of Lymphotropic Nanoparticles for accurate nodal staging

Radiology, Radiographics and AJR Researchers who develop Prostate MR Thanks to: Arifa Sadaf Radiology, Radiographics and AJR Researchers who develop Prostate MR

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