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The Prostate 35:50–55 (1998)
Diagnoses Rendered on Prostate Needle Biopsy
in Community Hospitals
Michael H. Weinstein,1* David L. Greenspan,2 and Jonathan I. Epstein2
1
Department of Pathology and Laboratory Medicine, University of Kentucky College of
Medicine, Lexington, Kentucky
2
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland
BACKGROUND. Reported incidences of various diagnoses made on needle biopsy of the
prostate vary significantly in the literature, most of which has originated from large, academic
medical centers.
METHODS. We recorded all the prostate needle biopsy results from three community hospitals for 1990–1993 to determine the rates of, and trends in, various diagnoses in these
practices.
RESULTS. Hospital H1 (1,192 cases) halved the rate of atypical, nondefinitive diagnoses from
11.8% in 1990 to 5.7% in 1993 (P < 0.001). The rate at H2 (2,792 cases) remained essentially
unchanged at 5.95 ± 0.55%, and H3 (1,306 cases) went from 2.3% to 6.0% (0.1 < P < 0.2). In the
setting of an atypical, nondefinitive diagnosis, H1 and H2 recommended repeat biopsy less
than 7% of the time. H3 made this recommendation in an average of 22.1% of atypical cases.
Annual rates of high-grade prostatic intraepithelial neoplasia (PIN) showed no trend over
time, and averaged 2.0% (1.2–3.25%) at H1 and 1.2% (0.3–2.0%) at H2. The diagnosis was
never made at H3. The fraction of cancers diagnosed as low-grade (Gleason sum ø4) showed
a statistically significant decreasing trend over time at all three hospitals (P < 0.05). These data
are compared with those from the Johns Hopkins Hospital (JHH), a large academic center in
geographic proximity to hospitals H1–H3.
CONCLUSIONS. At these three community hospitals, we discerned (1) convergence to a rate
of approximately 6.0% of atypical, nondefinitive diagnoses; and (2) a progressively more
appropriate fraction of carcinomas diagnosed as low-grade on needle biopsy. The rates of
diagnosis of high-grade PIN and recommendation of repeat biopsy varied. These rates of PIN,
atypical, nondefinitive diagnoses, and low-grade cancer represent an assessment of diagnostic
habits. Prostate 35:50–55, 1998. © 1998 Wiley-Liss, Inc.
KEY WORDS:
prostate cancer; prostatic intraepithelial neoplasia; atypical; Gleason
grade
INTRODUCTION
The last 5–10 years have seen an increase in the
number of needle biopsies of the prostate performed
in the United States each year. This has been due to
widespread screening for prostate cancer by measurement of serum prostate-specific antigen (PSA) concentration, as well as a burgeoning awareness of this disease. While the amount and grade of adenocarcinoma
of the prostate seen on needle biopsy are of some use
in predicting the extent of disease found in subsequent
prostatectomy specimens, even limited cancer on
needle biopsy may be associated with moderate to
large amounts of unsampled cancer in the whole
© 1998 Wiley-Liss, Inc.
gland. Therefore, the goal of pathologic examination
of biopsy material continues to be the identification of
every patient with adenocarcinoma of the prostate
without erroneously labeling anybody who is free of
cancer of the prostate.
Surgical pathologists have also begun to identify
markers seen on needle biopsy, such as high-grade
*Correspondence to: Michael H. Weinstein, Department of Pathology and Laboratory Medicine, University of Kentucky College of
Medicine, MS 117, Chandler Medical Center, Lexington, KY 405360084. E-mail: mweinst@pop.uky.edu
Received 19 May 1997; Accepted 7 August 1997
Community Hospital Diagnoses on Prostate Needle Biopsy
prostatic intraepithelial neoplasis (PIN), that indicate a
great likelihood of carcinoma within the gland. It has
become common for a nondefinitively malignant diagnosis to be rendered that suggests an increased likelihood of unsampled or inadequately sampled carcinoma. This usually leads to repeat biopsy. Physicians
in community hospitals administer a great fraction of
the primary health care, and there is a paucity of published information regarding their habits of diagnosis
for needle biopsy of the prostate. We concentrated in
this study on three main aspects: rates of atypical,
nondefinitive diagnoses; rates of diagnosis of highgrade PIN; and habits of grading of adenocarcinomas
of the prostate.
MATERIALS AND METHODS
The record of every set of needle biopsies of the
prostate examined from 1/1/90 to 12/31/93 by the
departments of pathology at three Baltimore–Washington area community suburban hospitals was obtained by computer search and entered into a database
(Paradox, Borland International, Scotts Valley, CA).
The demographics (e.g., age, racial/ethnic background, financial resources) of the populations served
by these three suburban hospitals are subjectively
similar. There were a total of 1,192 cases, each comprised of a set of needle biopsies, from the first community hospital (H1), 2,792 cases from the second
(H2), and 1,306 from the third (H3). The database was
used to tally statistics on several diagnostic categories.
We tallied diagnoses of atypia suspicious for carcinoma, atypia of unspecified character, and atypia
probably benign. It was not our purpose to assess the
diagnostic accuracy of the interpretation of these
needle biopsies, but rather to delineate the diagnostic
habits and extent of variation at these community hospitals. Hence, we did not perform a histologic review
of any of their material. Even had we wanted to review slides from these hospitals, none would have
permitted this exercise because of the potential medicolegal risk. Cases were counted as atypical, indefinite
for carcinoma when the report was neither benign, nor
definitively malignant, nor PIN. That is, there was a
concern expressed that some of the glands in the biopsy might be malignant, but no specific diagnosis
was given. In cases in which an outside consultation
had been requested, we recorded the original diagnosis. Thus, cases initially diagnosed as atypical, indefinite for carcinoma were recorded that way, even if
subsequent consultation lead to a definitive diagnosis.
Recommendations for repeat biopsy were counted, as
were diagnoses of adenocarcinoma of the prostate of
each Gleason score. Also tallied were diagnoses of
51
PIN, which fell into six categories: grades 1–3, highand low-grade, and unspecified grade. We grouped
diagnoses of PIN 1 with those called low-grade to give
our category of low-grade PIN. We also grouped diagnoses of PIN 2, PIN 3, and high-grade PIN to give
our category of high-grade PIN. Diagnoses of atypia
were counted only in the absence of any carcinoma in
the same set of biopsies, and PIN was counted only if
there was no concurrent diagnosis of atypia or carcinoma. The Gleason grade assigned to each case with
carcinoma was the highest of the grades given to any
of the needle biopsies in the set.
Statistical analyses were performed using the chisquare statistic for trend analysis.
RESULTS
We obtained records of all the needle biopsies of the
prostate performed from 1/1/90 to 12/31/93 at the
three community hospitals studied. There were 1,192
sets of needle biopsies at the first community hospital
(H1), 2,792 at the second (H2), and 1,306 at the third
(H3). The average number of biopsies per case (set)
was difficult to assess because of incomplete information in some of the reports, but was approximately 2 at
each of the three hospitals. Tabulation of the diagnoses is given in Tables I–III.
Table I lists by year and category the diagnoses of
atypia in the absence of a concurrent diagnosis of carcinoma. Note that the fraction of biopsy sets that were
diagnosed as atypical, indefinite for carcinoma varied
in 1990 from 2.3% at H3 to 11.8% at H1. The range
shrank in each of the succeeding three years, so that by
1993 only 5.7–6.3% of all biopsies carried the diagnosis
of atypical, indefinite for carcinoma.
Table II lists by year and grade the diagnoses of PIN
in the absence of concurrent carcinoma or atypia of
other type. At H1 and H2, the relative frequencies of
the diagnoses of high-grade and low-grade PIN varied
over the years, without a discernible pattern. They
made the diagnosis of high-grade PIN in 1–2% of
needle biopsies in most years. Hospital H3 did make
the diagnosis of low-grade PIN in 0–1.6% of needle
biopsies, but never diagnosed high-grade PIN. The
least common diagnosis at all three hospitals in every
year was PIN of unspecified grade.
The greatest change in the fraction of carcinomas
labeled as low-grade occurred at H1, as seen in Table
III. In 1990, 28.0% of all the sets of needle biopsies with
carcinoma at H1 were graded as Gleason score 2–4.
Hospitals H2 and H3 made the diagnosis of low-grade
carcinoma in 9.0% and 5.7% of the carcinomatous sets
of needle biopsies seen in that year. By 1993 the frac-
52
Weinstein et al.
TABLE I. Percentage of Total Cases Diagnosed as Atypical, Indefinite for Carcinoma and Rates of Recommendation
of Repeat Biopsy in These Cases by Year and Hospital*
Hospital H1
Atypia, favor benign
Atypia, unspecified character
Atypia, favor malignant
Total atypical diagnoses by year
Recommendations for repeat Bx
Total cases
Hospital H2
Hospital H3
90
91
92
93
90
91
92
93
90
91
92
93
2.0
5.3
4.5
11.8
0
247
2.7
4.5
3.0
10.2
2.9
334
1.0
1.5
2.7
5.2
4.8
404
1.4
1.9
2.4
5.7
0
207
1.2
2.1
2.4
5.7
0
328
0.9
3.2
1.3
5.4
0
685
1.3
2.7
2.5
6.5
3.6
1268
1.4
3.1
1.8
6.3
6.2
511
0.5
0.9
0.9
2.3
40.0
222
1.5
3.0
1.0
5.5
27.3
404
0.8
1.9
1.7
4.4
6.2
361
0.3
4.4
1.3
6.0
21.1
319
*There was a statistically significant trend in the fraction of total cases diagnosed as atypical at H1 (P < 0.001).
TABLE II. Percentage of Total Cases Diagnosed as PIN by Year and Hospital
Hospital H1
LG PIN
HG PIN
Unspecified grade
Total no. of cases
Hospital H2
Hospital H3
90
91
92
93
90
91
92
93
90
91
92
93
2.0
1.2
0
247
2.8
2.1
0.3
334
1.5
3.2
0.2
404
0.5
1.5
0
207
0.6
0.3
0.3
328
0.7
2.0
0.6
685
0.9
1.5
0.4
1268
3.6
1.0
0.4
511
0
0
0
222
0.2
0
0
404
0
0
0
361
1.6
0
0
319
HG PIN, high-grade PIN; LG PIN, low-grade PIN.
TABLE III. Percentage of Total Cases of Adenocarcinoma Assigned Each Gleason Score and Percentage of Total
Cases Diagnosed as Cancer by Year and Hospital*
Hospital H1
Gleason scores
2–4
5–6
7
8–10
Carcinoma of any grade
Total no. of cases
Hospital H2
Hospital H3
90
91
92
93
90
91
92
93
90
91
92
93
28.0
39.0
14.6
18.4
33.2
247
27.8
44.3
13.4
14.5
29.0
334
6.8
50.0
18.2
25.0
32.7
404
1.3
40.8
34.2
23.7
36.7
207
9.0
51.7
23.6
15.7
27.1
328
7.5
58.8
26.9
6.8
23.4
685
1.5
64.5
27.5
6.5
25.6
1268
2.3
65.9
26.4
5.4
25.2
511
5.7
37.7
41.5
15.1
23.9
222
2.9
53.9
32.4
10.8
25.2
404
3.6
50.0
28.2
18.2
30.5
361
1.9
47.6
32.0
18.5
32.3
319
*The trend in the fraction of carcinomas diagnosed as Gleason score 2–4 over 1990–1993 was statistically significant at H1 (P < 0.001)
and H2 (P < 0.001), but not at H3 (P > 0.3).
tion of malignant needle biopsies with Gleason score
2–4 only varied from 1.3% at H1 to 2.3% at H2.
DISCUSSION
The ability to interpret thin needle biopsies of the
prostate has increased considerably during the past
several years. The advent of immunohistochemical
staining for high-molecular-weight cytokeratin has allowed pathologists to reliably identify very small collections of atypical glands as carcinoma, and expertise
has increased to the point where this tool is often not
necessary even in some very small foci. However,
there do remain a significant number of biopsies with
atypical glands that cannot be characterized definitively as either benign or malignant. There are multiple reasons for this. Not only are the biopsies themselves small, but the foci in question are very small
and are not likely to be present on deeper levels obtained for the purpose of immunohistochemical staining. Few laboratories are willing to routinely obtain
unstained intervening sections on every needle biopsy
in case special stains are required. Second, many laboratories have limited capacity to perform immunohistochemical stains. Even under the best possible cir-
Community Hospital Diagnoses on Prostate Needle Biopsy
cumstances some lesions cannot be characterized with
certainty, since failure of staining for high-molecularweight cytokeratin to demonstrate basal cells in a
small focus of atypical glands is not itself diagnostic of
carcinoma.
The goal in the present diagnostic milieu of examination of needle biopsies of the prostate is to identify
every patient with adenocarcinoma of the prostate.
We are willing to have some patients who do not have
carcinoma be rebiopsied because of a focus of atypical
glands that are not identifiably benign with certainty.
However, unnecessary biopsy is clearly undesirable,
so it is important to keep the number of nondefinitive
diagnoses low. These conflicting demands require that
each pathologist set a threshold for the diagnosis of
‘‘atypical, indefinite for carcinoma.’’
In 1990, the diagnosis of ‘‘atypical, indefinite for
carcinoma’’ was made in 11.8% of the sets of needle
biopsies seen at hospital H1. There was a statistically
significant trend, with the rate going from 11.8% in
1990 to 5.7% in 1993 (P < 0.001) (Table I). The rate was
essentially constant at H2 from 1990 to 1993 (5.95 ±
0.55%), and there was a fluctuating but overall slightly
increasing trend at H3 from 2.3% in 1990 to 6.0% in
1993 (0.10 < P < 0.20). Personal communication suggests these changes may be due, at least in part, to
self-education of the pathologists rendering these diagnoses. Means of education may have included attendance at conferences, interdepartmental consultation, verification by immunohistochemical stains for
high-molecular-weight cytokeratin, and the accumulation of experience in interpreting needle biopsies of
the prostate.
Although there may be some variation between the
patient populations seen at these three hospitals that
are located in the same geographic area, they appear
grossly similar. The large number of needle biopsies
included in this study (5,290) implies that a large number of patients were screened. Consequently, these
data can be expected to be fairly representative of a
large segment of the pertinent population in terms of
variables such as serum PSA concentration and patient age. By way of comparison, recent data from the
Johns Hopkins Hospital (JHH), a large academic center in geographic proximity to the three community
hospitals in this study, indicated a rate of ‘‘atypical,
indefinite for carcinoma’’ diagnoses of 4.6% in 439
consecutive sextant needle biopsies seen there from
1/1/92 to 7/15/94 [1]. This slightly lower rate may be
due to one or more of several conflicting factors. One
reason for the lower rate may be that the number of
biopsies in each set at JHH was six, instead of the two
that were usual in the sets of biopsies performed during the time period of this study at the three community hospitals. More biopsies increase the likelihood
53
that a carcinoma in the gland will be sampled in a
fashion that permits a definitive diagnosis. On the
other hand, more biopsies make it more likely that a
small, atypical focus that is difficult to categorize will
show up in one of the needle biopsies of a set. At JHH,
H+E-stained sections are routinely obtained on three
levels for every needle biopsy of the prostate performed there. Unstained slides of sections from intervening levels are also obtained, making it more likely
that a section of a difficult lesion will be available to
stain for high-molecular-weight cytokeratin. This was
not routine at the three community hospitals. It is of
course possible that there is a referral bias, and that
the patient populations differ more than is apparent.
Finally, one of the authors of this study (J.I.E.) has
extensive experience in prostate pathology, including
an active consultation practice, and he reviews most of
the problem cases at JHH.
It is clear from Table I that there was no standardization on recommendations for repeat biopsy when a
diagnosis of atypical, indefinite is made. The likelihood of finding carcinoma on repeat biopsy depends
heavily on the threshold for making the diagnosis of
‘‘atypical, indefinite for carcinoma.’’ It is the experience of the authors of this work in reviewing consult
material that the frequency of such diagnoses varies
considerably from one institution to another, implying
a variation in threshold. We consider it appropriate to
recommend repeat biopsy in all cases that are suspicious but not diagnostic for prostate cancer. We reason
that the same clinical indications that warranted the
initial set of needle biopsies still pertain. In fact, there
is more cause for concern, since the pathologist has
recognized something in the initial biopsies that may
likely represent carcinoma. The morbidity of needle
biopsy is quite low [2], and generally is not a significant factor in this decision.
High-grade PIN is known to be a marker for the
presence of carcinoma, and should be reported if
found on needle biopsy in the absence of clear-cut
malignancy. There are several reports detailing the
risk of unsampled adenocarcinoma of the prostate
when a needle biopsy of the gland contains highgrade PIN [3–7]. It is generally agreed that this risk is
approximately 33–50%. However, it is clear that if the
accepted diagnostic criteria for high-grade PIN are not
adhered to and more cases are included, then the diagnosis becomes less meaningful. Published data reporting the incidence of high-grade PIN are scarce,
and the reported incidences vary. In one study, 25,000
men were screened by measuring serum PSA concentration, and 0.15% of them were found on needle biopsy to have high-grade PIN without carcinoma on
any of the biopsies in the initial set [6]. Another study
included biopsies from an academic center and a pri-
54
Weinstein et al.
vate practice laboratory and reported rates of 16.5%
and 9.5%, respectively, of high-grade PIN on needle
biopsy in the absence of atypia or identifiable carcinoma [8]. A third study reported a rate of 5% in consult material [9], and a fourth found an incidence of
11% in men with hypoechoic lesions of the prostate
[10]. Recent data from JHH yielded an incidence of
5.5% [1]. Notably, this study from JHH included review of all 439 cases, which disclosed an additional
2.8% of the cases that met criteria for high-grade PIN
over and above the reported rate of 2.7%.
Table II shows that the rate of diagnosis of highgrade PIN hovered around 1–2% at hospitals H1 and
H2 for most of the study period, and the averages over
the four years were 1.7% and 1.4%, respectively. By
contrast, hospital H3 never made the diagnosis of
high-grade PIN, and this probably represents underreporting. High-grade PIN has been shown to be a
reproducible diagnosis in two recent studies [11,12].
The first of these studies demonstrated a good degree
of interobserver agreement in differentiating between
low-grade PIN and benign on the one hand and highgrade PIN on the other [11]. Low-grade PIN was diagnosed in approximately 1% of the cases seen at H1–
H3, and there were a few cases of PIN of unspecified
grade. The diagnosis of low-grade PIN is not reproducible and has not been shown to be of clinical significance [3,6]. A diagnosis of PIN of unspecified
grade is problematic and probably should not be
made.
Left untreated, many lesions histologically identifiable as adenocarcinoma of the prostate will never lead
to clinical disease. We are limited in our ability to
discern which lesions are biologically benign but that
have a histologically malignant appearance. One feature well known to be important in predicting behavior is the Gleason sum of the tumor. Some patients
with tumors of Gleason sum <5 on needle biopsy and
low PSA densities are now, with the advice of their
physicians, electing to be cared for with ‘‘watchful
waiting’’ and no definitive therapy. Therefore, correct
identification of those patients with low-grade tumors
is important. As with high-grade PIN, reported rates
vary. One group found that none of 67 consecutive
patients who underwent radical prostatectomy with
needle biopsy available for review had tumors of
Gleason sum ø4 either on needle biopsy or in the
corresponding radical prostatectomy specimens [13].
Another found that 14% of their patients had lowgrade tumors on needle biopsy with a corresponding
rate of 3% in the prostatectomy specimens [14], and a
third group [15] found that 12% of their radical prostatectomy specimens had carcinomas of Gleason
sum ø4. It is possible that these differences are due to
differences in patient populations, but we believe it is
likely that they are due, at least in part, to differences
in judgment on the parts of the pathologists. The experience of the authors (based on the consult material
of J.I.E.) is that some pathologists factor the quantity of
tumor present in an needle biopsy into the grading
process. However, a very small focus of small,
crowded, well-formed glands clearly infiltrating between larger, benign glands should be categorized as
Gleason pattern 3, regardless of the quantity. We have
seen that it is not rare for a lower grade to be assigned
in such a situation. Probably more common is a consistent difference in the grade given to each pattern. In
order to apply the findings contained in the published
literature, interobserver reliability in Gleason grading
is necessary.
Though data are scarce, it is probable that the
threshold for the diagnosis of low-grade adenocarcinoma of the prostate (Gleason sum ø4) on needle biopsy should be set so that, in most patient populations, no more than approximately 5% of patients with
cancer are classified as having low-grade lesions [13–
16]. This number accurately reflects the fraction of
low-grade carcinomas seen in radical prostatectomy
specimens, in which more tumor is visible for accurate
grading. The fraction of low-grade cancers seen in
TURP specimens is higher, and, indeed, it is known
that transitional zone carcinomas tend to be of lower
grade. Table III shows a wide spectrum among the
hospitals in the fraction of carcinomas seen on needle
biopsy that were labeled as low-grade (Gleason
sum ø4) in 1990. The fraction ranged from 28% at H1
to 5.7% at H2. This difference is unlikely to be completely attributable to differences in patient population. The proportion of low-grade tumors steadily decreased at H1 to 1.3% in 1993. The trend from 28% in
1990 at H1 to 1.3% in 1993 was statistically significant
(P < 0.001) Similar, though less dramatic decreases
were seen at the other two hospitals, with the trends
being statistically significant at H2 (P < 0.001) but not
at H3 (0.3 < P < 0.5). Thus, in 1993, the range among
the three hospitals was 1.3–2.3%. The series of consecutive needle biopsies at JHH contained 3.9% that
were categorized as low-grade adenocarcinoma [1]. In
the cumulative experience with radical prostatectomy
specimens from 721 patients at JHH, the fraction that
had tumors of Gleason grade 2–4 was 6.8% [16]. This
is a greater fraction than was reported on needle biopsy at any of the three hospitals, H1–H3, in 1993, and
the difference is difficult to interpret. There may be
some limitations in reproducibility for the Gleason
grading system.
CONCLUSIONS
We found a temporal convergence among three
community hospitals in the rates of ‘‘atypical, indefi-
Community Hospital Diagnoses on Prostate Needle Biopsy
nite for carcinoma’’ diagnoses to approximately 6% of
all sets of biopsies. Similarly, the fraction of carcinomas labeled as low-grade also converged over the 4
years of the study period. The rates in 1993 were all
approximately 1–2%. High-grade PIN, the diagnosis
of which may still be in a state of evolution, was found
in approximately 1–2% of the sets of biopsies seen at
two of the community hospitals and was never diagnosed at the third during the four years that were
studied. This is a lower number than would be expected based on data from several academic institutions. These data represent an early step in assessing
practice patterns, and in most respects approximate
that obtained from a series of sextant needle biopsies
seen at JHH, a large academic center in geographic
proximity to the three hospitals studied here.
Similar studies involving larger numbers of institutions from varied locations may be valuable in defining the extent of variation in the diagnostic habits of
pathologists [17]. The authors recognize that the identification and limitation of diagnostic variation (reproducibility) is beneficial. We also recognize that diagnostic accuracy is a related but different attribute of
testing that requires validation, ideally by reference to
patient outcomes [18]. Additional efforts at standardization of diagnostic criteria as well as education appear to be warranted.
55
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