Advances in MR Imaging of PROSTATE CANCER

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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

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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

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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

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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

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HISTOPATHOLOGICAL TYPES

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

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SCREENING

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

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PSA (Prostatic Specific Antigen)

• Secreted into blood stream by the prostate gland
• Its 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)

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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 lt 25 of PSA is free worrisome for cancer

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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 ???

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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

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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

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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 2030
  over traditional number of biopsies
• Some centers recommend 24 biopsies (12 per side)
• to get ve diagnosis
• to accurately grade the tumor

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PATHOLOGYGleason GRADE and Gleason Score

• Gleason Grade ? 1Low .. 5High

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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 (34 vs 43)

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

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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

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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)

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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)

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WHO NEEDS MRI STAGING

• Staging MR would be cost effective if performed
• ONLY in the subgroup of patients with
• Palpable tumor
• PSA gt 10
• At least 50 positive cores for malignancy
• High Gleason grade and score

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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)

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NORMAL ANATOMY
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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

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ABNORMAL GLAND
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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

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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

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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 lt5
  of tissue resected
• T1b Tumor incidental histologic finding in gt5
  of tissue resected
• T1c Tumor identified by needle biopsy (eg,
  because of elevated PSA)
• T2 Tumor confined within prostate
• T2a Tumor involves lt 50 of 1 lobe
• T2b Tumor involves gt 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

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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) lt 2 cm
• N2 One or more regional lymph nodes, largest gt 2
  cm but lt 5 cm
• N3 One or more regional lymph nodes, largest gt 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)

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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.

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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

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LOCAL STAGINGT STAGING
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LOCAL STAGING

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

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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

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MRI SIGNS OF UNRESECTABLE DISEASE ( TNM Stage gt
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

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EXTRACAPSULAR EXTENSION - ECE
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ECE

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

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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

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SEMINAL VESICLE INVASION
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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

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BLADDER RECTAL INVASION
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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

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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)

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DYNAMIC CONTRAST ENHANCED MRI DCE MRI
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WHY TUMORS ENHANCE DIFFERENTLY THAN NORMAL TISSUES

• Cancers results in tumor angiogenesis
• Increased no. of vessels
• Increased permeability of vessels
• Increased interstitial tissue space

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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

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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

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DCE MRI Analysis of data

• 3 methods of analysis
• Qualitative ? Easier
• Look at curves
• Semi-Qualitative ? Average
• Parameters from curves
• Quantitative ? Complicated
• Mathematical Modelling

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MR SPECTROSCOPY - MRS
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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.

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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

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TUMOR VOLUME
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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

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TUMOR VOLUME

• Another study - ECE in 18 with vol. lt 3 cc
• 79 with volume gt 3 cc
• Tumor volume significant predictor of ECE
• Bx, TRUS and T2-MRI disappointing in volume
  estimation
• MRS provides more accurate volume estimation

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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

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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

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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

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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

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LOCAL STAGING N STAGING
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ABNORMAL NODES

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

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SHORTCOMINGS- NODAL STAGING

• Normal sized nodes - contain cancer as micro
  metastases
• Enlarged nodes may be reactive

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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

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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)

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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

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Thanks to

• Arifa Sadaf
• Radiology, Radiographics and AJR
• Researchers who develop Prostate MR

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Thank You