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The Importance of Percentage of Gleason Grades 4 Plus 5 in Predicting
Biochemical Recurrence in Prostate Cancer (June 2005)
In the management of this disease the ongoing challenge is
accurately predicting the future behavior of prostate cancer based on a
better understanding of its basic biology. In the May 1, 2005, issue of
the JCO Liang Cheng and colleagues from Indiana University make a
contribution to that effort by analyzing clinical outcome as related to a
critical analysis of Gleason grade in whole mount prostate specimens. In
their article, “The Combined Percentage of Gleason Pattern 4 and 5 Is the
Best Predictor of Cancer Progression After Radical Prostatectomy” they
present data supporting the conclusion: “The combined percentage of
Gleason patterns 4 and 5 is one of the most powerful predictor of patient
outcome, and appears superior to conventional Gleason score in identifying
patients at risk of disease progression”. This is not a new concept. It
has been extensively examined and convincing presented by Drs. Stamey and
McNeal in many articles during the 1990’s, but the Cheng report adds
useful detail by highlighting the importance of the percentage of
involvement by high-grade disease thereby focusing attention upon the
biologic and clinical significance of the critical histologic transition
from the abortive, but recognizable, gland formation seen in the lower
Gleason grades to the architectural disruption of grades 4 and 5.
Cheng’s evaluation took note of the previously recognized
facts that “two or more separate adenocarcinoma foci were present in 87%
of radical prostatectomy specimens”, that “there often was extensive
histologic heterogeneity among tumors within the same specimen” and that
“more than half contain three or more Gleason patterns”. Using whole mount
specimens they calculated the total area of all grades of cancer and
estimated volume of cancer in the entire specimen. They then summed the
individual areas of Gleason grades 4 and 5 in all the tumor sites and
derived the percentage of total cancer represented by this aggregate
amount of high-grade cancer. The results were tabulated as 5% increments
from 0% to 100% Gleason grade 4/5.
Their study was based on 364 men, treated only with
surgery, and followed closely for a mean of 14 months [a follow-up report
with longer follow-up would be helpful]. Biochemical recurrence was set at
a post surgical PSA value in excess of 0.1 ng/mL.
The key graph shows that over the follow-up range of 1.5 to
48 months there was a smooth increase in PSA recurrence in seven
designated groupings: 5.4% recurrence in those men with 0% or 1%-10% grade
4/5 cancer; 10% recurrence in the group having 11-30% grade 4/5; 21% with
11-30%; 30% with 51-70%; 50% in the 27 men with 71-90%; and 100% in the
two men with 100% grade 4/5.
As was earlier determined by Stamey and McNeal, increasing
tumor volume was tightly correlated with increasing histologic grade and
worsening clinical outcome. As expected, clinical outcome was correlated,
but to a lesser extent, with the customary morphological parameters and
also with the preoperative PSA.
However, the most predictive factors were tumor volume and percentage of
Gleason grade 4/5, with greater than 30% of Gleason grade 4/5 cancer
representing a useful breakpoint.
Especially informative are two summary articles by Stamey,
McNeal et al. presenting their ten or so years of research that
established the critical importance of the extent of Gleason 4/5 cancer.
In “Biological Determinants of Cancer Progression in Men
with Prostate Cancer”, JAMA April 21, 1999, Vol. 281, 1395-1400 they state
that their constant goal has been “to find better ways to distinguish
patients who have clinically innocuous cancer from those who have
significant disease that can be eradicated by radical prostatectomy or
other treatment and those for whom therapy is destined to fail”. This
study, with a median follow-up of 5.73 years, was based on 379 men who
underwent surgery and had no additional therapy until PSA recurrence, set
at > 0.07 ng/mL. Their method was to determine the percentage of Gleason
4/5 grade cancer in the largest tumor and concluded that “the %
Gleason grade 4/5, cancer volume, positive lymph nodes, and intraprostatic
vascular invasion were independently associated with cancer progression”
and the first two were most significant. The percent of Gleason grade 4/5
proved to be a more powerful predictor than the convention Gleason grading
system.
A figure was developed to illustrate the “increase in
failure rates as a function of the percentage of Gleason 4/5 cancer”. A
smooth increase in recurrence was seen with each 10% increase in
percentage of Gleason grade 4/5, from less than 5% recurrence at the O%
level to nearly 90% at the 91-100% level. Tumor volume also was a “highly
significant and independent determinant of biochemical failure”. PSA
recurrence developed in 14% of men with a tumor volume of 0.5 to 2.0 cc3;
39% for 2.0 to 6.0 cc3; 67% for 6 to 12 cc3; and 97% for men with tumors
larger than 12 cc3.
In a additional article, J Urol April 2000, Stamey, McNeal
et al. evaluated the relative significance of the conventional
morphological variables as predictors of PSA recurrence and again
identified the percentage Gleason 4/5 and tumor volume as the primary
determinants of treatment failure. The preop PSA
was important; vascular invasion less so; and in the context of this study
“capsular penetration, positive surgical margins, and seminal vesicle
invasion were insignificant”, i.e. not independent causes of biochemical
failure.
Regarding information available from biopsies: “We have
shown that if enough biopsies are taken, there is an excellent
representation of the percent of Gleason grade 4/5 in the index (largest)
cancer”. It is the restless cells that leave home
... that is, those prostate cancer cells that
comprise the histologic grades 4 and 5. The importance of these higher
grades is reflected in studies that show in a qualitative sense the worse
performance of men with Gleason sums 4 + 3 versus 3 + 4 cancers. The
extent of pattern 4, comprised as it is of these aggressive cells, can
vary widely as a component of a Gleason sum 3 + 4 = 7 cancer, but when
extent of pattern 4 in a specimen exceeds 50% it becomes, by definition,
the primary Gleason grade. Stamey has pointed out “For a score of 7, the
proportion of Gleason grade 4 cancer may vary between 5% and 95% without
altering the score (sum)”.
Current reporting has recently transitioned from the
practice of entering the second most prevalent histologic
pattern as “secondary” Gleason pattern. Now, if the worst grade is not the
most prevalent pattern, the worst grade - independent of its prevalence in
the specimen - is listed as the “secondary pattern”. This is a qualitative
acknowledgement of the importance of those restless cells - those
cells that have acquired the metastatic phenotype. Stamey, McNeal,
and Cheng would argue for taking that acknowledgement one step further and
replacing standard Gleason reporting by a quantitative statement of the
percentage of Gleason grade 4/5 in a specimen.
These collective determinations emphasize the importance of focusing
research on identifying the basis for this critical transition from the
more “benign” cancer cells that comprise the abortive glands of the lower
Gleason grades to the inherent aggressiveness of the cells of Gleason
grade 4/5 cancer. Stamey has urged that “research efforts at the genetic
and enzymatic molecular levels clearly should be directed at the Gleason
grade 4 cancer”.
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