1. 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

2. 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

3. 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

4. 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

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

6. 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

7. 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)

8. 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

9. 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 ???

10. 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

11. 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

12. 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

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

14. 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)

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

16. 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

17. 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

18. 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)

19. ( 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)

20. 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

21. 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)

22. NORMAL ANATOMY

23. 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

24. ABNORMAL GLAND

25. 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

26. 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

27. 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

28. 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

29. 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.

30. 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

31. LOCAL STAGING T STAGING

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

33. 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

34. 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

35. EXTRACAPSULAR EXTENSION - ECE

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

37. 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

38. SEMINAL VESICLE INVASION

39. 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

40. BLADDER & RECTAL INVASION

41. T2WI – SENITIVITY AND SPECIFICITY
Varies widely for cancer detection
Without endorectal coil
Sensitivity : 45 %
Specificity : 73 %
With Endorectal coil
Sensitivity : %
Specificity : %

42. 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)

43. DYNAMIC CONTRAST ENHANCED MRI – DCE MRI

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

45. 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

46. 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

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

48. MR SPECTROSCOPY - MRS

49. 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.

50. 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

51. TUMOR VOLUME

52. 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

53. 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

54. 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

55. 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

56. 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

57. 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

58. LOCAL STAGING N STAGING

59. 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

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

61. 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

62. 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)

63. 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

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

65. Thank You