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Gleason Score Upgrading From Biopsy To Prostatectomy Specimen
(January 2008)
The classic conundrum:
identify those who will benefit from treatment while sparing those who
don't need it ... at least not at the time of initial diagnosis. This
goal has given rise to the strategic option of "expectant management" in
which treatment is deferred while still retaining the possibility of
cure. As a result of increased PSA screening and greater public
awareness of prostate cancer, the demographics of prostate cancer has
experienced a seismic shift so that possibly well over 70% - 80% of the
130,000 or so new cancers are now Stage T1c. CaPSURE data indicates that
now half of patients in their recent database (increased from 11% in
1989) can be classified as "low-risk" based on D'Amico's definition:
biopsy Gleason score <6, PSA <10 ng/mL, and clinical stage
T1 or T2a. Among these low-risk patients are many with low PSA, low
grade, and low volume cancers, often termed "insignificant", that might
well exhibit indolent behavior. Men with this presentation of cancer are
candidates for "expectant management" in which the decision for future
treatment depends on subsequent information. But the trick is how best
to find, and with the greatest certainty, those men bearing these
potentially indolent tumors.
There is general
agreement that prostate cancers harboring Gleason pattern grades 4 or 5
should be considered for active treatment. Dr. Jonathan Epstein's
canonical definition of "insignificant" cancer on biopsy excludes
Gleason 7 cancers, and allows, taken together, only a pre-biopsy PSA
density of < 0.15 ng/ml/cm3; Gleason score of 6 or less with
no pattern grade of 4 or 5; no more than 2 cores positive for
cancer, and no more than 50% of any core involved with cancer. The
predictive expectation for men with this constellation of biopsy
characteristics is the strong likelihood that their prostate harbors a
tumor of <0.5cm3 confined to the gland with no Gleason 4 or 5
components.
Therefore, the issue of
Gleason upgrading from the biopsy diagnosis to the final
pathology on the surgical specimen is crucial in making the best
management decision. Biopsy Gleason score 6 cancers, combined with a
very few Gleason fives, are now the most common presentation - the new
Partin tables show that 77% of recent biopsy diagnosed cancers
are Gleason score 5 or 6. An informed prediction regarding the risk of
upgrading to Gleason score 7 is a necessity. Many studies have shown
that the final surgical pathology following prostatectomy upgrades
Gleason grade 6 in a variable 20% to 40% of instances.
Until an accurate
predictive panel of biomarkers is developed, clinicians must work in the
realm of probable risk. Currently, there are no reliable criteria to
determine which biopsies will be upgraded. Studies have suggested a
variety of predictive factors weighted as to their importance.
"Predicting the Risk of
Patients With Biopsy Gleason Score 6 to Harbor a Higher Grade Cancer",
Gofrit et al., J Urol, Nov 2007, reported 20.3% upgrade among 448
patients. In men with PSA values greater than 12 ng/ml the risk of
upgrade was 62%, and was 18% for PSA values less than 12 ng/mL. Among
this 18% "The risk [of an upgrade] was 22.6% and 10.5% when the greatest
percent of cancer in a core was higher than 5% versus 5% or lower,
respectively." Ninety-seven percent of upgrades were to Gleason score 7,
with 83% to Gleason grade 3 + 4 and 17% to 4 + 3. This relatively low
rate of upgrading probably resulted from the extent of biopsy sampling:
all men had more than 8-9 cores, 28.8% had 10 or 11, and 65% had 12 or
more cores. No significant influence was found for "patient age,
clinical stage, PSA density, disease bilaterality, and the percent of
positive cores." The combination of these parameters allowed a
prediction rate for upgrading "as high as 62% and as low as 10.5%."
A skeptical opinion
challenging the claims of accuracy for predicting true "insignificant"
cancers from biopsy parameters was voiced by a group from Emory
University in their article, "'Insignificant' prostate cancer on biopsy:
pathologic results from subsequent radical prostatectomy," Prostate
Cancer And Prostatic Diseases (2007) Oct. They argued that the most
accurate prediction for an insignificant tumor required addition
information about PSA velocity (PSAV) and clinical tumor stage. They
cited Patel's finding (JCO 2005 Sep) that a pre-biopsy PSA
velocity of > 2ng/ml/yr was associated with tumors > 1 cm3 in 86% of men
and predicted for advanced stage cancer with > 10% grade 4/5 on final
pathology, and a median time to relapse of 16 months post prostatectomy.
Their review of 800 cases in 11 studies found that all required a
clinical stage of T1c as one criterion for "insignificance."
Considering that
multiple parameters, each to an varying extent, influence the risk of an
upgrade in Gleason score from biopsy to surgical specimen, the
estimation of risk is nicely suited to a nomogram. "Clinical Predictors
of Gleason Upgrading", Kulkarni, Fleshner et al., CANCER JUNE 15,
2007, presents such a nomogram based on 175 low-risk cancers treated
with radical prostatectomy. Eleven elements, each weighted for its
significance, were incorporated: age; PSA, DRE, PIN, volume, TRUS
findings, number of cores (6 vs >10), percentage of cancer in the total
biopsy specimen, and the experience of the pathologist. All elements
contributed to an extent in appraising the risk, but interestingly, on
univariate analysis only a PSA value of >6.5 ng/mL (P=.02), and
the "the level of pathologist expertise" (P=.007) were significant.
Cited was a study that found 47% "undergrading to Gleason 7 tumors by
general pathologists."
In the Kulkarni study
34% of patients were upgraded to higher grade disease. Although this
nomogram has not been externally validated, the authors believe they
have "presented a nomogram that can serve as a useful adjunct when
counseling patients with low-risk disease" as to their management
options.
"Expectant management"
will increasingly be a reasonable strategy for the many men who are
being diagnosed with cancers with low PSA values, low volume, and low
Gleason grade, but the choice of this course must be made with proper
consideration of the issue of biopsy Gleason score upgrading.
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