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Multi-focal Prostate Cancer (April
2003)
The consensus from pathological studies is that PC most times presents as
multiple sites within the prostate. This has implications relating to
biopsy strategy, and, at a fundamental level, has potential for
understanding the genesis of the disease. Studies of glands removed for
incidental reasons (such as with a cystectomy) or in the treatment of
known prostate cancer find multiple sites of disease in 50% - 76% of
specimens. In a study conducted at Stanford and reported by Wise (joined
also by Stamey and McNeal: UROLOGY 60;(2)2002,p 264) only 17% of 486
glands had a single foci, 16% had two, and the remaining had from 3 to 12
independent sites. Another study (Miller GJ, J UROL 1994; Nov) reported
solitary lesions in 43% of 151 glands, two lesions in 31.1%, and the
remaining 25.2% containing 2 to 6 tumors. Djavan in 1999 found
multifocality in 66.9% of 308 specimens, with 63% having two lesions, and
37% three or more.
What else do these studies reveal?l) The
Wise study found that when multifocality exists the size of the largest
tumor decreases as the number of additional sites increases. After
contemplating this relationship the authors were led to consider whether
tumors might enlarge by accretion, "swallowing up" the surrounding smaller
tumor sites, particularly in the small confines of the peripheral zones.
The secondary tumors were mostly small, >.5 cm3 in 58% of the
observations. (Another study found 80% of the secondary lesions < .5 cm3).
Wise's follow-up results indicated that the risk of biochemical relapse,
however, was related to the size and grade of the largest tumor. Their
follow-up results led them to speculate that multiplicity was in some way
protective since patients with multifocal disease had better outcomes than
patients with solitary lesions when those patients' largest tumors were of
similar size.2) The Miller study found "that tumors need not acquired
either large volume or high grade before they" invade through the
prostatic capsule. Among capsule invading tumors of less than 3 cm3 there
was an equal division between those with Gleason sums of 2,3, and 4 and
those of 5,6, and 7. Contrary to Wise (above) Miller's opinion was that
multifocality adversely affected prognosis. 70% of the organ confined
tumors less than 1 cm3 had a Gleason sum of 4 or less.
Several thoughts arise from the fact of
frequent multifocality. Considering the relatively small size of a biopsy
specimen, sampling error is lessened by more probes into a potentially
multifocal tumor field. Currently there is a worthwhile effort to try to
relate the risk of treatment failure to the "number of positive biopsy
cores", but the randomness of hitting or missing additional tumor sites
will challenge the statistical strength of this association. (Dr. Kattan
is currently attempting to include this factor in the Partin Tables). A
study by Mazal (Eur Urol, 2001, June) addressed the issue of spacial
distribution of multiple prostate cancers. Prostatectomy specimens from
men whose initial biopsies were negative revealed biopsy-undetected tumor
most frequently in the apical region (p<0.001) and the the dorsal region
(p<0.01).
Ruijter (J Pathol 1996 Nov, and 1999
July) probed the issue of multifocality deeper by studying the
histological relationship among a prostate's various tumors. In the 1996
study whole mount prostatectomy specimens for 61 T2 prostate cancers were
mapped for histological grade heterogeneity and tumor multifocality.
Multiple tumors occurred in 72% and only 16% showed a single histologic
grade. Extracapsular invasion was often associated with tumors of small
volume and low histological grade. Variability of histological grade was
directly proportional to the total tumor volume. The 1999 study attempted
to further the analysis by using sophisticated molecular biological
techniques to examine for clonal concordance among tumors. This proved to
be a very challenging effort. Some individual tumors contained several
distinct clones, and among tumors in a single prostate specimen the
various tumor sites often showed a mixture of clonal similarity and
difference. Their conclusion was that "no clear evidence was obtained for
either a clonal or a non-clonal origin of multiple lesions in a given
prostate".
Since there is strong support for the
hypotheses that high-grade prostatic intraepithelial neoplasia (HGPIN) is
a precursor to cancer, it's possible that the study of this lesion may
provide clues to the "first three minutes" of the genesis of small
emerging galaxies of early cancer in the multi-billion cell universe of
the prostate gland. Bostwick, by studying chromosome regularity (karyometry)
among the nuclei of a single HGPIN lesion found evidence that even at this
stage there were differences in chromosome numbers. A Spanish researcher
compared chromosome features between HGPIN and PC in a single prostate and
found that in 75% the two lesions shared abnormalities of chromosome 7 and
8, common know abnormalities. And to make the analysis even more
complicated an Italian pathologist found nuclear abnormalities in
normal-looking cells adjacent to and distant from sites of HGPIN and PC.
Bottom Line: Application of advanced analytic techniques to the study of
tumor multifocality will move us closer to an understanding the genesis of
prostate cancer.
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