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| Under-detection of clinically significant prostate cancer resulting from TRUS-guided biopsies. |
Imaging based detection and MRI guided in-bore biopsy and diagnosis
This report was written by Bill Lewis. A DVD of the talk and presentation slides for this talk will be available 4/15/17 for purchase at IPCSG
Dr. Cooper started with a review of the state of diagnosing prostate cancer, including its
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| Over-detection of insignificant prostate cancer resulting from TRUS- guided biopsies |
However, current widely-used methods of screening for prostate cancer are leading to "over diagnosis" (excessive attention given to tumors very unlikely to ever become life-threatening) and over treatment. The current gold standard of diagnosis is a TRUS (trans-rectal ultrasound) biopsy, typically involving a dozen painful insertions of sampling needles, which sample only about 1% of the prostate overall, and entirely miss sampling a large portion of the prostate (due to the use of relatively short needles, and avoiding the area near the urethra due to fear of damaging it). As a result, 30-35% of the time, the patient is falsely thought to be free of tumors, and 35-45% of the time, those tumors that are found are thought to be less dangerous than they really are (that is, they are assigned a falsely low Gleason score). Typically, whole gland therapy (radical prostatectomy or irradiation of the entire prostate) is given, which leads to morbidity (that is, unpleasant side effects such as incontinence or impaired sexual function). And although many patients are put on "Active Surveillance," 25% of them harbor undetected prostate tumors that should be actively treated.
Dr. Cooper's goal is to find "Clinically Significant" prostate cancer. This is defined as comprising a tumor that poses a significant risk to health. A so-called "index tumor," has a tumor volume of more than 0.5 ml (about 1/10th of a teaspoon) and/or a Gleason pattern of 4 or 5 (i.e., very abnormal-looking cells found in the biopsy). Any tumors outside the "capsule" of the prostate (i.e., in the seminal vesicles or lymph nodes, bones or other tissues) also signify that the cancer is clinically significant. By correctly identifying if the cancer is clinically significant, then such cancers would be treated, but clinically insignificant ones would not be treated, thus avoiding morbidity (side effects) and expense.
The failure in the current reliance on TRUS biopsies is not that we are identifying too few cancers, but that we are identifying "too many." Many tumors are being unnecessarily treated.
Predictors of prognosis include the clinical stage at the time of diagnosis, from T1 to T4. However, these stages are outdated by many decades. T1 refers to tumors detected only in tissue removed during a TURP procedure ("reaming out" of the urethra to improve urine flow) or other prostate surgery. T2 means confined to the prostate, but detectable by palpation through the rectum (How primitive is that??). T3 means spread beyond the prostate "capsule." And T4 means it has invaded other nearby structures.
The Gleason score, a classification of prostate cancer aggressiveness on the basis of morphological characteristics, has provided the best predictor so far of patient outcome, despite many efforts at analyzing molecular and genetic expression. Visual examination of biopsy specimens -- for how abnormal the cells appear, using a pictorial reference chart to assign pattern number 1 (normal) through 5 (extremely abnormal), and then adding the pattern numbers for both the "dominant" (most often seen) and the secondary pattern, gives the "Gleason Score."
In 2005, the scoring was modified to cease reporting any pattern 1 or 2, and to change the sum to be the addition of the primary pattern plus the highest number pattern present. Thus, if 70% of the biopsy sample corresponded to pattern 3, 20% to pattern 4, and 10% to pattern 5, under the old system the Score would be 3+4=7, but now the score would be reported as 3+5=8. If only one pattern is present, the Score would be twice the pattern number; i.e., 6, 8, or 10. Also note that a 4+3 Score would be considered more serious than a 3+4 score, though in both cases the sum = 7.
There are no documented cases of a Gleason Score = 6 "cancer" (and Dr. Cooper along with many others believes that this should not even be classified as cancer) turning into metastatic disease.
The prostate gland is shaped like an upside down pyramid, starting in young adulthood at about the size of a walnut, and gradually enlarging. It has two main zones: The peripheral zone on the outside, comprising 70-80% of the tissue, with most of the rest considered the central zone, with some transition zone. The base is near the bladder, and the apex is the point at the bottom. Toward the back on both lower sides is the neurovascular bundle; damage to which causes sexual dysfunction and incontinence.
Most tumors occur in the peripheral zone (consistent with its comprising most of the prostate), but more of the remaining tumors are found in the transition zone than in the central zone. Only the peripheral zone is reached in most TRUS biopsies.
Digital rectal exams identify the presence of a tumor in only 14-28% of men with prostate cancer. The PSA test is indicative, but very non-specific (with interference from other causes), and TRUS biopsies have huge problems with accurately detecting prostate tumors, discussed in the talk.
In contrast, MRI can provide an accurate test to detect, localize (and 85% of the time, there is more than one tumor), stage (determine if the disease is confined to the prostate or not), and guide the biopsy of the disease. A study published in 2011 showed 98-100% accuracy in detecting tumors using mpMRI, and sensitivity was highest with the most serious tumors (as is appropriate), as confirmed by subsequent removal and biopsy of the prostate.
Multiparametric-MRI (mpMRI) consists of a number of computer-aided detection processes: T2-weighted images, useful for finding transition zone tumors; DWI (diffusion-weighted image) & ADC (apparent diffusion coefficient) for peripheral zone tumors; Axial T1 (for overall anatomy and to see the neurovascular bundle); and DCE (dynamic contrast enhancement).
In an MRI, a magnetic field 15-30,000 times as strong as the earth's magnetic field is used to cause the protons to line up in one direction. Then a radiofrequency pulse (similar to FM radio waves) is uses to "knock" some protons out of alignment. As they return to alignment, some energy is released and detected. The T1 and T2 parameters are based on this detected energy. If you like details, know that the T1 energy is the basic "return 90 degrees back into alignment," and the T2 energy is the slight wobbling, or “precessing,” of the spinning proton as it recovers from the pulse. It's the opposite of a spinning top falling over. If it fell straight down, that would be pure T1. But it wobbles and gradually falls closer and closer to the ground. The wobbling is T2, but the overall falling is T1. Got it? It turns out that one signal is better for some purposes (e.g., T2 to see tumors in the transition zone), and the other is better for other visualization (i.e., overall anatomy, including the neurovascular bundle).
The DWI & ADC show and measure the rate of diffusion of water within the tissue. The tissue in peripheral zone tumors is more dense than healthy prostate tissue, so the movement of water molecules is restricted enough to be detected (DWI) and even quantified (ADC). If the diffusion coefficient is below 900 mm2/sec, it is strong evidence of a tumor, and the value correlates very well with the Gleason Score! Dynamic contrast enhancement (DCE) refers to images obtained as a tracer chemical injected into the patient is rapidly taken up preferentially by tumor cells, and then also quickly released back into the bloodstream. The tumor is highlighted in a bright red color, in the images generated by the software.
Regarding the hardware, Dr. Cooper explained that the differences between 1.5T and 3T (strength of the magnetic field) images, and studies with or without the endorectal coil (somewhat better images, but uncomfortable to the patient and more expensive), all are washed out by the issue of how well the machine is "tuned."
A number of Prostate Cancer cases detected by mpMRI were shown, with their various images. The procedure for MRI-guided biopsy was described, including how it can be used to precisely guide the needle into the suspicious areas identified in the diagnostic mpMRI. Patients (including this writer) report that it is practically non-painful, in great contrast to reports of traditional TRUS biopsy pain. (Trivia note: An 18-gauge needle is used, and gauge means "how many needle barrels fit side-by-side in an inch).
Tumors of Gleason Score 9-10 were easily and straightforwardly found in MRI-guided biopsies, where no tumor had been found in 2-5 prior TRUS biopsies, in four examples shown. A published study in Urology in 2010 showed that in 71 consecutive patients with PSA higher than 4 ng/ml, and at least two prior negative TRUS biopsies, that an mpMRI diagnosis and MRI-guided biopsy found cancer in 60% of these men. More importantly, 93% of the tumors were "clinically significant." Also, more than half of the tumors were in the apex or anterior side of the prostate, where TRUS biopsies don't reach.
Here's the contrast: TRUS biopsies miss 30-35% of prostate cancers. mpMRI misses only 3% of Gleason Score 4+3 tumors, and only 10% of 3+4 tumors. TRUS biopsies under-grade the Gleason Score 35-45% of the time. mpMRI with MRI-guided biopsy under-grades only 5% of the tumors (based on subsequent biopsy after prostate removal).
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| Current and proposed diagnostic pathways |
A new technique is promising: The UroNav system uses an mpMRI diagnostic image superimposed on a trans-rectal ultrasound image, to localize the suspected tumors for biopsy. The ultrasound image can show where the prostate is, and can give real-time images of where the biopsy needle is. The superimposed image shows where the tumor is. This may give even more accuracy than the current MRI-guided biopsy procedure, which requires sliding the patient in and out of the machine, to first take an image, then operate the needle insertion equipment, then put the patient back into the machine for the next view of the process. Dr. Cooper likes the new system, and would like to use it in his practice. A study published in 2015 showed that the UroNav system gave 30% more detection/diagnosis of high-risk cancers, and desirably less detection of low-risk cancers, than standard biopsies. Still, the tumor detection yield to date is best with MRI-guided biopsy.
Cash costs for mpMRI at Imaging Healthcare Specialists are $400 without contrast (if the patient is allergic to the contrast agent), or $575 with contrast agent injection. For an MRI-guided biopsy, the cash cost is $1600, but may be covered by Medicare at 100%. (Cost questions? Call Tami Colbert at 858-658-6416.)
Questions: What if you can't have an MRI? Reasons would be an old-type pacemaker, or a surgical clip in the brain, but most clips in other parts of the body would be OK. Axumin PET/CT (very recently FDA approved, and used a dozen times so far by Dr. Cooper) and PSMA scan technologies were explained as possible alternatives.
The expense of medicine going up is partly due to doctors purchasing expensive imaging equipment, then "overusing" it to increase their billings. The Deficit Reduction Act tried to counter this by reducing payouts for scans.
MRI after radiation? The radiation is terribly damaging, so the images are not as distinct as otherwise. And usually in those cases, a whole-body scan is appropriate.
PIRAD is an acronym, "prostate imaging reporting and data" system, developed from BIRAD reporting of breast cancer, to standardize reports. The system can be learned about online, or from additional slides from Dr. Cooper that are included with the video that will be available for purchase online or at our next meeting. The BIRAD system is used at Imaging Healthcare Specialists, and at several other organizations in our area.
The extra slides also cover "problems" with Gleason Scores, and the new 2016 WHO Gleason grading system, which has Grade Groups from 1 to 5, corresponding to Gleason Scores "6 or less," 3+4, 4+3, 8 and "9-10."
The role of MRI in detection, localization and staging is summarized in the extra slides. An intriguing slide listed four options for treating prostate cancer: Active Surveillance (for Gleason Score 6 when PSA <10 and="" beam="" biopsy="" brachytherapy="" by="" cryotherapy.="" ditto="" external="" localized="" low="" mpmri="" mri-guided="" on="" or="" prostate="" prostatectomy="" radical="" span="" style="mso-spacerun: yes;" the="" to="" undetectable="" volume=""> That last warrants extra explanation. And what about other local therapies that might be guided by MRI or UroNav, such as NanoKnife?
The American Urologic Association guideline statements (five in all) were summarized. The updated statements from 2013 were also summarized.
Final slides: TRUS: Who gets biopsied? PSA explained, with both positive and negative issues. PSA velocity and density explained. Again, all the extra slides are included with the video that can be purchased for $10.
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