Original Articles
ISOLATED HGPIN AND REPEAT BIOPSY
AKHAVAN
et al.
The proportion of cores with high-grade prostatic
intraepithelial neoplasia on extended-pattern needle
biopsy is significantly associated with prostate cancer on
site-directed repeat biopsy
Ardavan Akhavan‡, Jonathan D. Keith‡, Sheldon I. Bastacky*, Chao Cai†, Yun Wang†
and Joel B. Nelson
Departments of Urology, and *Pathology, University of Pittsburgh School of Medicine, and †Biostatistics, University of
Pittsburgh Cancer Institute, Pittsburgh, PA, USA
Accepted for publication 18 October 2006
‡These authors contributed equally
OBJECTIVE
To determine whether the predictive value of
isolated high-grade prostatic intraepithelial
neoplasia (HGPIN) for an unsampled prostate
cancer on an extended biopsy is lower due to
more thorough prostate sampling, and
whether the proportion of cores with HGPIN
is associated with prostate cancer, as isolated
HGPIN on sextant prostate biopsy is
associated with a 27–57% risk of prostate
cancer on repeat biopsy.
PATIENTS AND METHODS
All extended prostate biopsies taken by one
urologist over 6 years were reviewed for
patients with isolated HGPIN on initial biopsy.
Biopsies were evaluated for histological
features and the proportion of cores with
INTRODUCTION
High-grade prostatic intraepithelial neoplasia
(HGPIN) is characterized by atypical
proliferation of ductal and acinar epithelial
cells with preservation of the glandular
basal cell layer. The association between
HGPIN and prostate cancer is generally
accepted, with studies showing it to be a
stronger predictor of cancer than any other
variable [1]. Studies of autopsy and radical
prostatectomy (RP) specimens have shown
HGPIN to be present in 63–94% of
prostates with adenocarcinoma, and
25–43% of benign prostates [2,3]. When the
diagnosis of isolated HGPIN is made after
©
HGPIN. The clinical characteristics and
pathological findings from subsequent
biopsies were determined.
RESULTS
Of 577 men having extended biopsies, 48 had
isolated HGPIN, followed by one to four sitedirected repeat biopsies. Although only 10
(21%) had cancer on the first repeat biopsy,
overall 15 (31%) had cancer. Those with
cancer on repeat biopsy had a significantly
higher proportion of cores with HGPIN, i.e.
29% vs 15%, cancer vs no cancer, respectively
(P = 0.04).
proportion of cores with HGPIN on initial
biopsy was significantly associated with the
risk of cancer. The same was not true for age,
race, prostate-specific antigen level, or the
findings on digital rectal examination.
The significant association between the
proportion of cores with HGPIN and the risk
of cancer suggests that patients with unifocal
HGPIN on extended biopsy be managed
expectantly, whereas those with multifocal
HGPIN be re-biopsied.
KEYWORDS
prostatic intraepithelial neoplasia, prostatic
cancer, needle biopsy
CONCLUSIONS
Isolated HGPIN on extended biopsy conferred
a 31% risk of unsampled prostate cancer. The
sextant TRUS-guided prostate sampling, the
standard practice is to re-biopsy, as various
studies reported a 27–57% incidence of an
initially unsampled cancer on the second
biopsy [1,4,5].
Increasingly many practices have advocated
the use of more extensive biopsy sampling, as
obtaining more cores has been shown to
increase the rate of cancer detection by 35%
[6]. Given the more thorough sampling of the
prostate, it would be intuitive to assume the
diagnosis of isolated HGPIN would have a
higher negative predictive value for cancer
after an extended-pattern needle biopsy
than it would were it obtained in the
2 0 0 7 B J U I N T E R N A T I O N A L | 9 9 , 7 6 5 – 7 6 9 | doi:10.1111/j.1464-410X.2006.06681.x
standard sextant fashion. We report our
experience with site-directed repeat biopsies
after the diagnosis of isolated HGPIN on
extended-needle biopsies. We also
determined the predictive significance of
clinical factors, including race, PSA level,
age, DRE result, extent of HGPIN, histological
subtype, and presence of atypical small acinar
proliferation (ASAP).
PATIENTS AND METHODS
Institutional Review Board approval was
obtained to review the medical records of all
patients who had TRUS-guided prostate
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A K H AV A N ET AL.
TABLE 1 The characteristics of the 48 patients and the outcome results on univariate and multivariate analyses
Clinical
variable
Age, years
mean
median
range
PSA, ng/mL
mean
median
range
Cores with
HGPIN, %
mean
median
range
ASAP
no
yes
DRE
normal
abnormal
unknown
Race
Caucasian
African-American
unspecified
HGPIN histological subtype
flat
tufted
flat/tufted
unknown
Overall
(48)
First repeat biopsy result (n)
HGPIN (11)
Cancer (10)
Benign (27)
61.3
61
49–75
61.7
63
52.1–69.5
64.3
66.2
52.1–75.3
60
60.5
49.3–71.1
7.3
5.7
2.7–26.7
6.4
6.7
2.5–11.2
6.1
4.8
0.6–24.1
P
0.26‡
Final biopsy result (n)
Cancer (15)
No cancer (33)
62.8
63
52.1–75.3
60.6
60.6
49.3–71.1
8.8
7.2
2.5–26.7
5.4
4.7
0.6–24.1
0.43‡
6.5
4.9
0.6–26.7
0.32‡
19.2
17
7.0–75.0
16.6
17
7.0–36.0
28.2
18
8.0–75.0
17
17
8.0–50.0
43
5
10
1
8
2
25
2
30
17
1
8
3
0
6
4
0
16
10
1
41
3
4
10
1
0
9
0
1
22
2
3
2
33
10
3
5
1
3
2
8
0
2
0
20
1
5
1
28.5
19
8–75
15
17
7–44
12
3
31
2
11
4
0
19
13
1
12
1
2
29
2
2
12
0
2
1
21
2
8
2
0.48†
0.84†
0.92†
0.44†
P (univ)
0.27¶
P (MLR)
NA
0.03¶
0.181
0.06¶
0.04*
0.31†
NA
0.52†
NA
0.81†
NA
0.69†
NA
*Significant at P < 0.05; †Fisher’s exact test; ‡Kruskal–Wallis test; ¶Wilcoxon rank-sum test. MLR, multiple logistic regression analysis; NA, not applicable.
needle biopsies by one urologist (J.B.N.) and
isolated HGPIN with or without ASAP, on
initial biopsy (IRB# 0507148). All patients with
previous biopsies taken by another urologist
were excluded.
Between August 1999 and June 2005, 577
patients had 721 prostate needle biopsies; all
initial biopsies were taken in an extended
peripheral scheme. Seventy-eight patients
(14%) had HGPIN with no malignancy on
initial biopsy; 57 of these (73%) had no
previous biopsies and met the inclusion
criteria. All patients were offered immediate
re-biopsy; nine either refused the procedure
or were lost to follow-up, but the remaining
48 had at least one re-biopsy. All repeat
biopsies were site-directed, where three to
four cores were sampled from each area of
the prostate that was positive for HGPIN.
Thirty-seven patients had one repeat biopsy,
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nine had two, one had three, and one had
four. The decision to have further biopsies
depended on the PSA value, PSA velocity,
abnormal DRE finding, and/or the finding
of HGPIN on subsequent biopsies. Of the
48 patients, a median (mean, range) of 12
(12, 8–17) cores were sampled during the
initial biopsy.
One pathologist (S.I.B.) reviewed all 48 cases
for confirmation of initial diagnosis and
determination of histological subtype. The
extent of HGPIN was calculated as the ratio of
the number of cores with HGPIN to the total
number of cores taken. Age, race, DRE and
serum PSA level were also determined
retrospectively. Univariate and multivariate
logistic regression analysis was used to
determine the correlation between these
variables and the presence of cancer on
repeat biopsies.
Also, 728 randomly selected retropubic RP
specimens, resected over the same period by
the same surgeon (J.B.N.) for cancer, were
evaluated. The maximum diameter of the
dominant tumour, Gleason score, margin
status, seminal vesicle involvement, and
clinical stage were assessed and compared
with those of the resected prostate cancer
specimens from the HGPIN group.
RESULTS
The median (mean, range) age of all 577
patients was 62.1 (62.4, 40.6–88.4) years and
the PSA level before biopsy was 5.4
(11.8, 3.3–1329) ng/mL. The clinical variables
of the 48 patients in the study are shown in
Table 1, which also gives the results of first
repeat biopsies. Overall, 10 (21%) patients who
had isolated HGPIN on initial biopsy had
cancer on their first repeat biopsy. The time to
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2 0 07 B J U I N T E R N AT I O N A L
ISOLATED HGPIN AND REPEAT BIOPSY
Risk of prostate cancer
FIG. 1. The predicted risk from simple logistic
regression analysis of 48 patients.
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0 10 20 30 40 50 60 70 80 90 100
Proportion of cores with HGPIN, %
the second biopsy was 20 (41, 7–462) days,
with all but one patient having a repeat biopsy
by 49 days. Univariate analysis showed no
significant differences in any of the measured
clinical variables between patients who had
cancer, benign, or HGPIN on first repeat
biopsies. Reported P values are determined
from the analysis among all three categories.
The results of all repeat site-directed biopsies
for each patient were combined into the
categories ‘cancer’ and ‘no cancer’, the latter
consisting of patients with only benign or
HGPIN diagnoses (the last four columns of
Table 1). At the final repeat biopsy, 15 (31%)
of patients had adenocarcinoma. Final
biopsies were obtained at 28 (170, 7–1471)
days from the initial biopsy date. After
nonparametric univariate analysis, all
covariates significant at P < 0.07 were
evaluated in a multiple logistic regression
model. While age, race, PSA level, presence of
ASAP, HGPIN subtype and DRE result were no
different between the outcomes, the
proportion of cores with HGPIN on initial
biopsy was significantly higher in those with
cancer on final biopsy (P = 0.04).
A simple logistic regression analysis model
based on the 48 patients suggests that the
risk of finding cancer on repeat biopsy was
significantly related to the proportion of cores
with HGPIN (%HGPIN) found on initial biopsy
(P = 0.02), expressed as (e−2.05+0.06 × %HGPIN)/
(1 + e−2.05+0.06 × %HGPIN). Figure 1 shows this
predicted risk of having cancer, based on the
proportion of cores with HGPIN on initial
biopsy.
Of the 15 patients with cancer, 14 had a
Gleason score of ≤7; 11 had a retropubic RP,
and the remainder had (one each) either
external beam radiation with or without
brachytherapy, hormonal therapy, or were lost
to follow-up. The 11 RP specimens were
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Variable
Number
Tumour maximum diameter, cm
mean
median
range
Gleason score, n or n (%)
≤6
≥7
Staging
≤T2
≥T3
Margin status
negative
positive
Seminal vesicles
negative
positive
Sample
11
Overall
728
P
<0.01*†
0.69
0.6
0.2–1.8
TABLE 2
The characteristics of the
RP specimens
1.38
1.4
0.1–3.9
0.54‡
6
5
301 (41)
427 (59)
10
1
556 (76)
172 (24)
10
1
645 (89)
83 (11)
11
0
685 (94)
43 (6)
0.47‡
1‡
1‡
compared with those of 728 randomly
selected patients undergoing RP during the
same interval by the same urologist (Table 2).
In the sample the maximum tumour diameter
was 0.6 (0.7, 0.2–1.8) cm, significantly smaller
than the maximum tumour diameter for the
overall RP group (P < 0.01). No other
evaluated tumour characteristic was
significantly different between the groups.
DISCUSSION
HGPIN occurs as an isolated diagnosis in
0.7–24% of prostate biopsies [7,8]. When a
sextant biopsy yields isolated HGPIN the
standard practice is to re-biopsy, as reports
have cited a 27–57% incidence of cancer on
follow-up [1,4,5]. However, after extendedbiopsy sampling, studies report an incidence
of 2.3–11% cancer on the follow-up of
patients with HGPIN [2,9–11], thus
questioning the utility of re-biopsy. By
contrast, we found that 15 of 48 patients with
isolated HGPIN (31%) had cancer on
subsequent site-directed biopsies. Ten of the
15 cancers (21% overall) were discovered on
the first repeat biopsy. Our results are similar
to those of Roscigno et al. [12], who reported
a 44.6% incidence of cancer on repeat
extended biopsies, concluding that repeat
biopsies are warranted in patients with
isolated HGPIN.
By contrast with the present study, repeat
biopsies in these previous reports were taken
in the same extended pattern as the initial
ones [2,9–12]. While the present patients had
initial biopsies taken by an extended pattern,
*Significant at P = 0.05;
†two-sample t-test;
‡Fisher’s exact test.
repeat biopsies were site-directed, where
three to four cores were taken only from areas
with HGPIN on initial sampling. There are
several reasons why we used this practice. In
our cohort, all biopsies were taken by one
urologist who was confident of the location
of the HGPIN foci found initially. Also, by
limiting the number of cores sampled, the
urologist was able to minimize biopsyassociated morbidity. The appropriate rebiopsy strategy is controversial. Chan and
Epstein [13] found a significantly greater
incidence of malignancy in areas localized to
sites of atypical biopsy findings. Similarly, Park
et al. [14] found significantly greater rates of
cancer after site-directed repeat biopsies, but
also noted a 10–12% incidence of cancer at a
location away from the location(s) of the
initial atypical biopsy. Roscigno et al. [12]
reported a 24% incidence of remote cancer,
including a 14% rate of cancer on the
contralateral side. While these values support
an extended re-biopsy technique, 75–85% of
malignancies occurred in regions localized
to the original abnormal biopsy site. The
increased rate of cancer in regions of HGPIN
might explain the higher incidence of cancer
in our study. Also, our study was the first to
use one urologist and one pathologist,
thereby reducing inter-investigator variability
in sampling and analysis, respectively.
The interval to repeat biopsy is important
in the follow-up of patients with HGPIN.
Extending the interval allows for a
synchronous cancer to enlarge to a size that
would be more likely to be sampled on repeat
biopsy, but it also confounds the results, as
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A K H AV A N ET AL.
developing tumours might be metachronous
and not present when the HGPIN is initially
detected. Previous studies concluded that
there is a significant increase in the number of
cancers detected after a 6-month delay
between initial HGPIN diagnosis and repeat
biopsy [12]. Lefkowitz et al. [15] found that
patients with HGPIN on initial extended
biopsy had a 2.3% incidence of cancer at
1 year on repeat extended biopsy, and a rate
of 25.8% at 3 years. In the present study, the
urologist recommended that patients be rebiopsied immediately. While there were a few
‘outliers’ who had final biopsies taken at
>1 year after initial biopsy, the median time to
final biopsy was 28 days; thus, the cancers
detected were most likely unsampled
synchronous, rather than metachronous
tumours. This suggests that waiting for small
tumours to enlarge might be helpful, but
unnecessary.
We report that the proportion of cores with
HGPIN on initial biopsy correlated with the
chance of finding cancer on subsequent
biopsies. Prange et al. [16] reported that the
number of cores positive for HGPIN on
sextant biopsy corresponded with the total
volume of HGPIN in cystoprostatectomy
specimens. Furthermore, they showed that
the rate of cancer was also associated with
the number of cores positive for HGPIN on
initial sextant biopsy. Our results are again
similar to those of Roscigno et al. [12], who
concluded that, of the patients who had
cancer on repeat biopsy, 90% had multifocal
HGPIN on initial extended sampling. Our
model illustrates that an individual with one
of 12 cores positive would have a 17.2% risk
of having cancer detected on subsequent
biopsy, a rate similar to that reported from the
follow-up of initially normal biopsies [1,17].
Consequently, we recommend that those men
with unifocal HGPIN on extended biopsy be
followed conservatively with serial PSA levels
and DRE. Conversely, patients with multifocal
HGPIN should be re-biopsied immediately.
However, our study has an inherent bias;
patients with more HGPIN foci are more
extensively re-biopsied. This might artificially
inflate the correlation between the proportion
of cores with HGPIN and risk of cancer;
however, the previous studies of Prange et al.
and Roscigno et al. did not have the same
site-directed repeat biopsy bias, but still
reported a significant association between
the variables [12,16]. Importantly, the
proposed risk model might not be applicable
to patients whose clinical features vary from
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those of the 48 in the present study (Table 1,
first column).
Serum PSA levels were significantly different
between the groups with cancer and without
in the univariate, but not in the multiple
logistic regression, analysis. PSA levels might
be predictive of synchronous cancer in
patients with HGPIN; our small sample of 48
men limits our ability to dismiss any clinical
variable from having no predictive value. This
might also be the case with the presence of
ASAP, as only five patients had this on initial
biopsy. Previous studies showed that the
finding of ASAP with HGPIN is associated with
a significantly higher rate of cancer on rebiopsy than HGPIN alone [18]. The histological
subtype of HGPIN did not correlate with final
outcome either, a finding that might also be a
function of the sample size. Only two patients
had isolated flat HGPIN subtype, and none
had cribriform or micropapillary patterns.
Previous studies assessed the predictive
significance of the histological subtype of
HGPIN for prostate cancer on subsequent
biopsies. Most report no significant
differences in cancer rates between the
different morphological patterns; however,
Kronz et al. [19] reported cribriform and
micropapillary HGPIN subtypes to have a
higher positive predictive value after
univariate analysis of outcomes.
initially undetected cancers, while smaller
than those found on initial biopsies, are
histologically no less dangerous, further
supporting the notion that patients
with isolated HGPIN must be followed
aggressively.
In conclusion, we report that 31% of patients
with isolated HGPIN on initial biopsy had
prostate cancer on subsequent biopsy. The
incidence of cancer was directly associated
with the number of cores with HGPIN
involvement. Therefore, we recommend that
patients with multifocal HGPIN on initial
biopsy be re-biopsied immediately, whereas
those with unifocal HGPIN be managed
conservatively with serial estimates of PSA
level and DREs.
CONFLICT OF INTEREST
None declared.
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Of the cancers found on subsequent biopsy
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Correspondence: Joel B. Nelson, Frederic N.
Schwentker Professor & Chairman,
Department of Urology, University of
Pittsburgh Medical Center, Shadyside Medical
Building, Suite 209, 5200 Centre Avenue,
Pittsburgh, PA 15232, USA.
e-mail: [email protected]
Abbreviations: HGPIN, high-grade
intraprostatic intraepithelial neoplasia; RP,
radical prostatectomy; ASAP, atypical small
acinar proliferation.
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