Over the past few years, pathologists have taken on several important
roles in the assessment of adenocarcinomas of the prostate. First,
the availability of postoperative serum prostate-specific antigen
(PSA) levels and their establishment as a sensitive indicator
of progression following surgery have provided the impetus to
correlate pathologic findings with progression following radical
prostatectomy. The second major role pathologists play is in the
diagnosis of adenocarcinoma of the prostate. With the advent of
the thin needle biopsy gun and screening with serum PSA, there
has been a dramatic increase in the number of needle biopsies
performed to rule out adenocarcinoma of the prostate. Pathologists
are challenged to make diagnoses on these very limited tissue
specimens, as well as to accurately grade and quantify the tumor.
This article covers some of the more topical issues in the pathology
of prostatic adenocarcinoma, from its precursor lesions to invasive
carcinomas, from needle biopsies to radical prostatectomies. In
particular, the discussion focuses on practical aspects of pathology
that are critical for oncologists to know for the management of
Prostatic intraepithelial neoplasia (PIN) consists of architecturally
benign prostatic acini or ducts lined by cytologically atypical
cells. Initially, this lesion was termed "intraductal dysplasia,"
and was classified into three grades: PIN1 (mild dysplasia), PIN2
(moderate dysplasia), and PIN3 (severe dysplasia) . Most authorities
today use the term "high-grade PIN" to encompass both
PIN2 and PIN3 and "low-grade PIN" to denote PIN1.
Low-grade PIN should not be commented on in diagnostic reports.
First, pathologists cannot reproducibly distinguish low-grade
PIN from benign prostate tissue . Second, when low-grade PIN
is diagnosed on needle biopsy, patients are at no greater risk
of having carcinoma on repeat biopsy .
There are several reasons why PIN2 and PIN3 should be combined
as high- grade PIN. First, there is much interobserver variability
in the distinction between PIN2 and PIN3 . Second, the finding
of either PIN2 or PIN3 on needle biopsy is associated with the
same risk of carcinoma on subsequent biopsy.
In prostates with carcinoma, there is an increase in the size
and number of high-grade PIN foci, as compared with prostates
without carcinoma. Also, with increasing amounts of high-grade
PIN, there are a greater number of multifocal carcinomas .
Several studies have noted an increase in high- grade PIN in the
peripheral zone of the prostate, corresponding to the site of
origin for most prostate adenocarcinomas. A growing body of data
has demonstrated that the expression of various biomarkers in
high-grade PIN is either: (1) the same as in carcinoma, as opposed
to benign prostate tissue; or (2) intermediate between benign
tissue and carcinoma. All of the above findings are to be expected
if high-grade PIN is a precursor lesion to prostate carcinoma
High-grade PIN is most critical when found on needle biopsy. In
a consecutive series of sextant biopsies performed at Johns Hopkins
Hospital, the incidence of high-grade PIN without carcinoma on
needle biopsy material was 2%. However, other studies have reported
that up to 16% of needle biopsies show high-grade PIN. When high-grade
PIN is found on needle biopsy, there is between a 30% and 50%
risk of finding carcinoma on subsequent biopsies .
The presence of an abnormal rectal examination or an abnormal
ultrasound scan does not identify which patients are more likely
to have carcinoma on follow-up biopsies; on ultrasound, high-grade
PIN may appear indistinguishable from cancer as a hypoechoic lesion
. In men with high-grade PIN on needle biopsy, the one finding
that increases the likelihood that there is an unsampled carcinoma
is an elevated serum PSA density; PIN, by itself, does not give
rise to elevated serum PSA values .
A repeat biopsy should be performed when high-grade PIN is found
on needle biopsy. The significance of the finding of high-grade
PIN on transurethral resection of the prostate is more controversial,
as there are no follow-up studies in the literature. Some pathologists
recommend that needle biopsies be performed on patients who have
high-grade PIN on transurethral resection, although others recommended
needle biopsies only in younger men .
Histologically, PIN can be confused with several benign entities,
as well as ductal and acinar (ordinary) adenocarcinoma of the
prostate. Also, there are some histologic patterns that are diagnostic
of high-grade PIN to some pathologists and yet represent high-grade
PIN and associated adenocarcinoma to others . Ploidy does not
distinguish high-grade PIN from infiltrating cancer.
Lack of Data on Natural History
Unlike premalignant lesions in other organs, data are lacking
on the natural history of high-grade PIN. At present, there is
no way to monitor a PIN focus in the prostate to determine: (1)
whether or not there already is an infiltrating carcinoma at that
site; or (2) when infiltrating carcinoma evolves, whether it has
done so in the immediate vicinity of the PIN focus. Because we
do not know what percentage of patients with the biopsy finding
of high-grade PIN develop infiltrating carcinoma over a given
follow-up interval, most authorities do not use the term "carcinoma
in-situ of the prostate."
In addition, some data have raised questions about the relationship
of PIN to carcinoma. The majority of prostates with early carcinomas
lack any high-grade PIN. Also, when PIN is present in glands with
an early carcinoma, the intraepithelial neoplasia often is not
adjacent to the carcinoma . It appears that high-grade PIN
is a precursor lesion to many peripheral intermediate- to high-grade
prostatic adenocarcinomas. However, PIN need not be present for
carcinoma to arise. Low-grade carcinomas, especially those present
within the transition zone, are not closely related to high-grade
Despite this lack of information on the natural history of PIN,
it is hoped that suppression of PIN will lead to a long-term decrease
in prostate cancer. Based on the observation that potent antiandrogen
therapy (luteinizing hormone-releasing hormone [LHRH] agonists
and flutamide [Eulexin]) can decrease the extent of PIN, a large
chemoprevention trial sponsored by the National Institutes of
Health is currently attempting to determine whether use of a weaker,
less toxic hormonal therapy (ie, 5-alpha-reductase inhibitors)
will also have an impact on PIN and carcinoma .
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