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Regular Articles |
From the Departments of Pathology,*
Internal
Medicine,
and
Surgery,
Section of Urology, University of
Michigan, Ann Arbor, Michigan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. PAH is best known to the
surgical pathologist as a mimic of prostatic adenocarcinoma (PCA)
because of its overlapping architectural and nuclear features,
especially when these lesions are predominantly composed of
small-crowed glands with nuclear enlargement and prominent nucleoli.
Distinguishing PAH from PCA is particularly important on prostate
needle biopsy because of the therapeutic implications.
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Several recent studies have re-examined the role of PAH as a potential
neoplastic precursor.1,14-16
Two studies examining the
topographic location of PAH with respect to PCA concluded that PAH is
extremely common in the periphery of the prostate
gland.1,14
Immunohistochemical analysis has identified
some surprising features regarding PAH. First, Ruska and
colleagues16
demonstrated that prostatic atrophy including
PAH is not undergoing involution but instead is proliferative in nature
as determined by high MIB-1 expression by immunohistochemistry (Ki-67).
This confirmed previous observations by Feneley and
colleagues17
and Liavag.3
Second, De Marzo
and colleagues15
identified expression of the
carcinogen-detoxifying enzyme, 
-class glutathione S-transferase
(GSTP1) in the basal cell layer of benign nonatrophic prostatic
epithelium, which they believe protects cells from DNA damage.
Prostatic atrophy including PAH for the most part overexpresses GSTP1
except for focal areas, which have low or absent GSTP1 expression. They
concluded that the majority of prostatic atrophy is protected from
incurring DNA damage because of the protective role of GSTP1. However,
some of the secretory cells are potential targets for genetic
alterations and potentially neoplastic transformation. Finally, work
from Macoska and colleagues18
recently identified
chromosome 8p22 loss and 8 centromere (8c) gain in a small number
(n = 7) of atrophic lesions using interphase
fluorescence in situ hybridization (FISH).
This study examines PAH as a neoplastic precursor lesion by comparing topography, proliferation, and 8c gain between PAH, HGPIN, and PCA in a series of radical prostatectomies from men with clinically localized PCA.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Between the years 1996 and 1998, 632 patients underwent radical
retropubic prostatectomy as a monotherapy (ie, no hormonal or radiation
therapy) at the University of Michigan Hospital for clinically
localized PCA. Clinical and pathology data for all patients was
acquired with approval from the Institutional Review Board. From these
cases, 40 formalin-fixed and paraffin-embedded whole-mount radical
prostatectomies were randomly identified for the purposes of this
study. The preoperative and pathology data for all cases is summarized
in Table 1
. These cases are
representative of the larger population of cases; no statistically
significant differences between the 40 cases in the present study and
the 632 cases were seen (data not shown). Hematoxylin and eosin-stained
sections were evaluated for foci of simple atrophy (SA), PAH, HGPIN,
and PCA. SA was defined as large dilated glands with normal
architecture composed of lining epithelial cells with scant cytoplasm
and absence of nuclear enlargement or prominent nucleoli. PAH was
defined using previously described criteria.1
In brief,
PAH included dilated acini with adjacent small, crowed glands.
Architecturally these foci have a lobular, well-circumscribed
appearance at low magnification. High magnification demonstrated scant
to moderate amounts of cytoplasm, regular chromatin pattern, and
occasional nucleoli. Focal nuclear enlargement was also observed within
the microacinar foci of PAH. Foci demonstrating these features were
marked and analyzed for several parameters: 1) number of foci with SA
and PAH; 2) location within the prostate gland as peripheral or
transition zone; 3) association of SA and PAH with HGPIN and PCA as
adjacent, near, or distant (adjacent was defined as glands merging with
each other, near was defined as being within one high-power field from
each other and distant was defined as separated by more than one
high-power field); and 4) number of SA and PAH foci associated with
acute and chronic inflammation.
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Immunohistochemistry
Indirect immunohistochemistry was performed to evaluate
proliferation using the monoclonal mouse IgG Mib-1 antibody for Ki-67
(1:150 dilution; Coulter-Immunotech, Miami, FL). Microwave pretreatment
(30 minutes at 100°C in Tris-ethylenediaminetetraacetic acid buffer)
for antigen retrieval was performed using 3,3'-diaminobenzidine
tetrahydrochloride as a chromogen. Negative controls were derived by
omission of the primary antibody. Four slides per case
(n = 168 slides total) were evaluated for
proliferation index in areas of benign, SA, HGPIN, and PCA using a
digital image analysis system (CAS200; Bacus Labs, Lombard, IL).
Measurements were recorded as the percentage of total nuclear area that
was positively stained. All positive nuclear staining, regardless of
the intensity, was measured. Sites for analysis were selected to
minimize the presence of nonsecretory epithelium (eg, stromal and basal
cells). Each site contained 
50 to 100 epithelial nuclei.
Proliferation was measured from 5,510 sites.
Tissue Microarray Construction
To evaluate all lesions of interest on a single glass slide, a
tissue microarray was assembled using a manual tissue arrayer (Beecher
Instruments, Silver Spring, MD). This procedure has previously been
described.19,20
The instrument consists of thin-walled
stainless steel needles with an inner diameter of 600 µm and
stylet used to empty and transfer the needle contents. The assembly is
held in an X-Y position guide that is manually adjusted by digital
micrometers. In this technique, small biopsies were retrieved from
selected regions of donor tissue and transferred to a new paraffin
block. Tissue cores are 0.6 mm in diameter and range in length from 1.0
mm to 3.0 mm depending on the depth of tissue in the donor block. Cores
are inserted into a 45 x 20 x 12-mm recipient bock
(standard size) and spaced at a distance of 0.8 mm apart. After
construction, 3-µm sections of the resulting microarray block were
cut and a hematoxylin and eosin-stained slide was reviewed to confirm
that the targeted tissue was actually transferred into the tissue
array. Because of the small size of PAH and HGPIN lesions, only a total
of 17 cases (43% of 40 cases) were represented on the final tissue
microarray. The identity of each 0.6-mm tissue sample was tracked using
their coordinate (X-Y) position and linked to clinical and pathology
data on a relational database (Microsoft Access; Microsoft, Redmond,
WA).
FISH
FISH analysis for 8c gain was performed as previously described18,21-23 using the rhodamine-labeled chromosome 8 pericentromeric probe DNA as the 8c probe (CEP8 Spectrum Orange DNA Probe; Vysis Inc., Downer’s Grove, IL) on formalin-fixed, paraffin-embedded tissue cut at a thickness of 5 µm. Standard slides and tissue microarray slides were used to optimize this protocol. As an initial control of nuclear ploidy, a pericentromeric DNA probe for chromosome 12 was used (CEP 12 spectrum green DNA probe, Vysis Inc.). Slides were incubated in 4 mg/ml pepsin (Sigma P-7012 in 0.9% NaCl, pH 1.5, Sigma Chemical Co., St. Louis, MO) at room temperature for 5 minutes. Slides were hybridized for 16 hours in a humidified chamber and then counterstained with DAPI II and visualized using appropriate fluorescent light filters (Zeiss Axioplan, Germany). Tissue microarray samples (0.6-mm diameter) were analyzed at x1,000 final magnification by counting the number of fluorescent signals in at least 100 nuclei per tissue microarray sample. Morphology was confirmed by bright-field microscopy before evaluating the next tissue sample.
Statistical Analysis
Using commercial software two nonparametric tests were applied. The Kruskal-Wallis (for more than two categories) and Wilcoxon ranked sum tests (for two categories) were used to determine differences between histological tissue types and test results (8c gain and Ki-67 expression).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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SA and PAH were both found frequently and topographically located
near or adjacent to PCA in the peripheral zone of the prostate gland.
Examination of 40 consecutive whole-mount radical prostatectomy
specimens revealed SA in 39 of 40 (98%) cases and PAH in 31 of 40
(78%) cases. SA foci (n = 129, mean 3.2/case)
and PAH foci (n = 114, mean 2.9/case) were
identified. Peripheral zone location, the most common site of PCA and
HGPIN was common for both foci of SA and PAH, yet PAH tended to be more
common. Seventy-four percent (95 of 129) foci of SA and 88% (100
of 114) of PAH were present in peripheral zone, respectively
(chi-square test, P = 0.006). There was a significant
difference between the number of SA and PAH foci located directly
adjacent and near to PCA, with 14% (18 of 129) and 28% (32 of 114)
foci of SA and PAH, respectively (chi-square test, P =
0.007). No such difference was noted for the number of SA and PAH foci
located directly adjacent to and near to HGPIN with 10% (13 of 129)
and 14% (16 of 114), respectively (chi-square test, P
= 0.3). Foci of PAH were more often associated with chronic
inflammation than SA, 43% (49 of 114) versus 29% (37 of
129), respectively (chi-square test, P = 002). These
results are summarized in Table 2
.
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The median Ki-67 labeling rate (ie, percentage of total nuclear
area staining positive for Mib-1) analyzed from >5,510 sites revealed
a progressive increase from benign to PCA (Table 3)
. As a base line, 1.20% (95%
confidence intervals 0.82 to 1.74%) of benign, nonatrophic prostate
glands demonstrated nuclear proliferation as determined by Mib-1
staining for Ki-67. A significant increase in nuclear proliferation
from normal prostate was seen along a continuum: SA (2.67%) <
PAH (3.62%) < HGPIN (6.14%) < PCA (12.00%)
(P < 0.001).
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FISH analysis was successfully performed on the tissue microarray
slide constructed with multiple replicate samples of benign prostate,
SA, PAH, HGPIN, and PCA. Fifty-one samples could be adequately
evaluated for 8c gain (Table 4)
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Chromosome 8 gain was divided into three groups ranging from zero to
two fluorescent signals, three signals (tri-ploidy), and greater than
three signals. A gain of more than three signals for 8c was observed in
1.3% of the benign nuclei. A gradual increase in the percentage of
nuclei with more than three signals for 8c was found for SA (2.1%),
HGPIN (2.8%), PAH (4.0%), and PCA (6.0%) (P =
0.006). Therefore significant 8c gain was observed more often in PAH
than in either SA or HGPIN.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Another important observation made by Anton and colleagues1 was the high degree of association between chronic inflammation and PAH. Chronic inflammation was present at 88% of the PAH foci. This was considerably greater than that of the 43% of PAH lesions with chronic inflammation seen in the present study and the 32% association identified by Ruska and colleagues.16
Ruska and colleagues16 renewed interest in the significance of prostatic atrophy by demonstrating that prostatic atrophy is not undergoing involution but is instead proliferative in nature as determined by the proliferation marker Ki-67 (Mib-1). This observation was confirmed by De Marzo and colleagues15 using prostatectomy specimens. The present study performed a global analysis of proliferation with >5,000 measurements. The results demonstrated a proliferative gradation going from benign prostate (1.20%), SA (2.67%), PAH (3.62%), HGPIN (6.14%), to PCA (12.00%). The present study found a significant difference in proliferation between each category, including SA and PAH. SA had a proliferation index of 2.67%, which was greater than benign prostate (1.20%), but significantly less than PAH (3.62%). The difference in proliferation between SA and PAH is compatible with their distinct histological appearances.
De Marzo and colleagues15
have attempted to link the
strong association with proliferative atrophic lesions and chronic
inflammation, noting that longstanding chronic inflammation seems to
predispose one to the development of carcinoma. In their study, they
combined focal SA and PAH, coining the term proliferative inflammatory
atrophy. They observed expression of the carcinogen-detoxifying enzyme,
-class glutathione S-transferase (GSTP1) in the basal cell layer of
benign nonatrophic prostatic epithelium; the induction of GSTP1 is
believed to protect cells from DNA damage. In contrast, the
secretory-type epithelial cells in proliferative inflammatory atrophy
(PAH and SA) overexpress GSTP1 except for focal areas, which have low
or absent GSTP1 expression. Therefore, according to their study, the
majority of proliferative inflammatory atrophy is protected from
incurring DNA damage because of the protective role of GSTP1; some of
the secretory cells, however, are potential targets for genetic
alterations and potentially neoplastic transformation.
We recently reported 8c gain in 7 atrophic lesions.18 The present study expanded on that observation by evaluating SA and PAH lesions using FISH for 8c gain. Interestingly, PAH demonstrated an increase in three fluorescent signals for 8c that was greater than SA or even HGPIN. One novel approach taken in this project was the development and utilization of a tissue microarray composed of targeted lesions. Therefore, we were able to assemble PCA, PAH, and benign tissue from the same case on the same slide, allowing better control of experimental variables, such as antibody binding and in situ hybridization efficiencies. Another potential benefit is that histologically benign epithelium adjacent to PCA may not be genetically normal. Perhaps more importantly, HGPIN adjacent to PCA may in instances represent intraductal spread of tumor and not discrete dysplastic lesions. Therefore our sampling method, taking lesions away from tumor, may avoid a field effect bias. This approach is in contrast to most studies looking at molecular alterations in HGPIN using FISH. These studies have confined their analysis to a single slide per case.18,24,25 The tissue microarray, as recently demonstrated by Bubendorf and colleagues,26 is also an efficient way to profile a large number of tumors.
8c gain has been reported to be a common molecular alteration found in HGPIN.25 8c gain in prostate tumors is believed to be a marker for poor prognosis.18,21,24,27 For example, Sato and colleagues24 reported that 34.7% (50 of 144) of stage III (T3N0M0) prostate tumors had 8c gain. Macoska and colleagues,18 recently reported a significant association between poor outcome and 8c gain. The mechanism for 8c gain was recently demonstrated to be because of isochromosome 8 formation with 8p loss.7,28 Putative proto-oncogenes on 8q29 and tumor suppressor genes on 8p8,11 have also been reported.
The present study found that PAH demonstrated a significant increase in
the percentage of nuclei with greater than three signals for 8c as
compared to HGPIN, SA, and benign prostate. This percentage was only
less than the 6.0% found in PCA. This observation along with the
proliferative data suggests that SA and PAH are distinct from one
another. However, they may represent a continuum in the process of
tumorogenesis. We believe that the absolute percentage for chromosome
8c gain may be underestimated because of inefficient hybridization. For
each sample, as described in the Materials and Methods section, at
least 100 nuclei were counted. There was a significant proportion
(70%) that demonstrated either one or no signals. This would
suggest that improvement in our ability to perform hybridization with
the 8c probe would demonstrate an even higher percentage of prostate
tissue with chromosome 8 gain. The present study also identified an
increase in the percentage of nuclei with trisomy for 8c in the
atrophic lesions (SA and PAH), HGPIN, and PCA with respect to benign
prostate. This difference was, however, not statistically significant
(P = 0.24). This lack of significance may be
because of an insufficient number of cases evaluated.
The findings of the present study build on previous work from Ruska and colleagues16 and De Marzo and colleagues.15 Prostatic atrophy is a common, histologically distinct entity found in the peripheral zone of the prostate. PAH is in a state of proliferation and not involution. PAH is often associated with chronic inflammation and PCA. PAH also demonstrates 8c gain, a molecular alteration often seen in HGPIN and PCA. These results support the earlier hypothesis by Franks2 that PAH or a subtype of prostatic atrophy is a neoplastic precursor. It is important to recognize that the evidence for HGPIN as the direct precursor to PCA is identical to findings of PAH and to a lesser degree SA. There is a spectrum of changes seen from SA to PAH and various studies have used slightly different definitions for PAH. For example, the present study has a broader definition of PAH that is more consistent with Anton and colleagues.1 Ruska and colleagues16 confined their study to include a narrow range of lesions and avoided lesions with overlapping features.
In conclusion, the present study identifies a strong topographic association between PAH and PCA. PAH is also seen often to be closely associated with chronic inflammation. Proliferation of PAH is significantly greater than benign prostatic epithelium and SA but less than HGPIN or PCA. Gain of 8c is significantly greater in PAH than benign prostate, SA, and even HGPIN. These findings demonstrate a strong association between PAH and PCA, supporting its role as a neoplastic precursor.
However, a number of questions still need to be answered. Does PAH give rise to HGPIN or directly to PCA? What is the role of inflammation in this process? Do random molecular events in PAH occur that cause a chronic inflammatory response? Or conversely does chronic inflammation produce these molecular alterations? Further studies using laser capture microdissection and expression array technology should help to more completely elucidate the relationship between PAH and PCA.
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Acknowledgements |
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Footnotes |
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Supported by the National Cancer Institute Special Program of Research Excellence (S.P.O.R.E.) in Prostate Cancer (grant CA69568). Presented in part at the United States and Canadian Academy of Pathology (New Orleans, LA., March 2000) and the American Urologic Association (Atlanta, GA., May 2000) meetings as poster presentations.
Accepted for publication February 5, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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