emedicine.medscape.com

eMedicine Specialties > Urology > Cancer, Prostate

Precancerous Lesions of the Prostate

Stanley A Brosman, MD, Clinical Professor,
Department of Urology, University of California at Los Angeles Medical
School

Updated: Apr 24, 2009

Introduction

Background

Prostate cancer is one of the most common malignancies diagnosed in
men and is the most common cancer found in men older than 60 years. One third or
more of all men older than 50 years have a latent form of prostate cancer that
may progress to life-threatening prostate cancer. The prevalence of latent
prostate cancer is similar among men of all cultures, races, and ethnic groups,
but the frequency of clinically active cancer is markedly different.

Environmental factors have been implicated in activating latent
prostate cancer. If cancer can be identified in an early or latent stage, the
neoplastic process may be reversed.

Prostatic intraepithelial neoplasia
(PIN), particularly high-grade PIN (HGPIN), and atypical small acinar
proliferation (ASAP) have been identified as precursor lesions to prostatic
carcinoma. PIN refers to the precancerous end of a morphologic spectrum
involving cellular proliferation within prostatic ducts, ductules, and acini.
Bostwick and Brawer introduced the term PIN in 1987.1 At an
international conference in 1989, the term PIN was accepted as a replacement for
various other terms (eg, intraductal hyperplasia, hyperplasia with malignant
change, large acinar atypical hyperplasia, marked atypia, ductal-acinar
dysplasia.)

Three grades of PIN were initially described; however, those
at the consensus conference agreed that only the terms low-grade PIN (LGPIN) and
high-grade PIN (HGPIN) would be used. Many pathologists no longer report the
presence of LGPIN and note only the histologic findings associated with
HGPIN.

High-grade prostatic intraepithelial neoplasia

HGPIN is characterized by architecturally benign prostatic acini and
ducts lined by atypical cells whose morphologic, histochemical,
immunohistochemical, and genetic changes are similar to those of prostate
cancer. HGPIN does not invade the basement membrane of the prostatic glands.
LGPIN may also be a precursor lesion but is no longer considered to be important
enough to be included in the pathologic description.

When HGPIN is
identified, the pathologist carefully searches tissue specimens for evidence of
cancer. Patients in whom HGPIN is found are usually advised by a urologist to
begin continued follow-up care with serum prostate-specific antigen (PSA)
testing, physical examination, and, possibly, repeat biopsies. An estimated 30%
of men with HGPIN develop clinical evidence of prostate cancer within one
year.

HGPIN itself is not considered to be a disease that produces
symptoms, nor does it require therapy. Although the general agreement is that
HGPIN is a potential harbinger for the development of clinical prostatic
adenocarcinoma, most experts agree that observation alone is safe for these
patients.

Atypical small acinar proliferation

ASAP is another
histologic entity that denotes a focus of atypical glands that are suspicious
for cancer. ASAP differs from HGPIN; thus, the two categories should not be used
interchangeably. The implication is that this is a specific lesion that is
analogous to HGPIN, but ASAP includes a group of lesions (eg, adenosis, atypical
adenomatous hyperplasia, intraductal hyperplasia, acinar atypical hyperplasia)
that have varying clinical significance. Some ASAP lesions mimic cancer, and, in
many instances, focal carcinoma may be present, but cytological, histochemical,
and architectural atypia are insufficient to establish a definitive
diagnosis.

The histologic findings of ASAP are characterized by the
presence of abnormal or atypical glands that have insufficient cytological or
architectural atypia for a definitive diagnosis of cancer. ASAP lesions have
been identified in 0.5-23% (mean, 5.5%) of patients undergoing needle biopsies
of the prostate. In patients with ASAP, the likelihood of finding cancer in a
subsequent biopsy sample is 40-50%.

This article reviews the current
approach for managing patients with HGPIN and ASAP and discusses their
relevance.

Pathophysiology

Bostwick et al have described 4 architectural patterns of HGPIN:
tufting, micropapillary, cribriform, and flat.2 Tufting is the most
common and is present in 97% of all HGPINs. Most histologic samples contain
multiple patterns, and the various HGPIN patterns carry equivalent
prognoses.

HGPIN spreads through the prostatic ducts in 3 patterns that
resemble prostate cancer. In the first pattern, neoplastic cells replace the
normal luminal secretory epithelium, but the basal layer and basement membrane
are preserved. Foci of HGPIN may be indistinguishable from ductal spread of
carcinoma when viewed with light microscopy. The second pattern is characterized
by direct invasion through the ductal or acinar wall with disruption of the
basal cell layer. In the third pattern, neoplastic cells invaginate between the
basal cell layers. This rare pattern is sometimes described as pagetoid
spread.

Some pathologists may note that a small focus of atypical glands
has been identified in a biopsy specimen but that, although the finding is
suspicious for cancer, not enough cytological or architectural atypia are
present to diagnose cancer. In this scenario, the pathologist usually suggests
that another biopsy be performed.

Clinically, the specific pattern and
morphologic features are not as important as the mere presence of either of
these entities. The clinical importance and the follow-up strategy depend on the
amount or number of biopsy cores that contain these lesions. In patients
diagnosed with prostate cancer, the finding of an associated HGPIN or ASAP
becomes irrelevant.

De Marzo and associates have suggested
that proliferative inflammatory atrophy, which may represent regenerative
epithelium in response to environmental insults, may precede the development of
PIN and early carcinoma.3 These lesions may arise in the setting of
inflammation and exposure to dietary toxins such as the carcinogens that have
been identified in charred meat.

Frequency

United States

The frequency of PIN in men with prostate cancer is significantly
higher than in those without cancer. The reported frequency of HGPIN alone
varies from 0.7-20%, which seems to depend on the pathologist and the number of
biopsies obtained. In an analysis of 17 studies, in which a total of 87,713
patients underwent biopsy, 3735 (4.26%) had HGPIN. The largest contributors to
this total were Orozco et al,4 with 62,537 patients (of whom 4.1% had
HGPIN), and Novis et al,5 with 15,753 patients (of whom 3.9% had
HGPIN).

Borboroglu et al reported cancer detection rates on repeat biopsy
ranging from 25-79% for HGPIN and 21-51% for ASAP.6

Eight
additional publications have reported the results of repeat biopsy. As many as
3446 patients were diagnosed, with cancer in 23% (range, 23-100%). Of this
number, O'Dowd et al contributed 3030 patients, with 23% diagnosed with
cancer.7

HGPIN appears to precede cancer by more than 10
years, with a parallel age-related increase in the frequency of HGPIN and
cancer. HGPIN has been found in 9% of men in the second decade of life, 22% of
men in the third decade, and 40% of men in the fourth decade. The prevalence of
HGPIN in men aged 80 years is 70%.

One of the criticisms of these
historical studies is that they evaluated data obtained using sextant needle
biopsies, which is no longer the standard technique. Current extended biopsy
schemes obtain more than 10 biopsy cores (usually 10-12) depending on the size
of the prostate. In some situations, saturation biopsies consisting of more than
20 cores are performed.

Moore et al evaluated the biopsy results of 105
men in whom repeat extended biopsies were performed to further evaluate a
finding of HGPIN or ASAP.8 In the HGPIN group, cancer was diagnosed
in 1 (4.5%) of 22 men based on first repeat biopsy results and in 0 of 11 based
on a second repeat biopsy result. The results in the ASAP group were much
different. The first repeat biopsy revealed cancer in 19 (36%) of 53 men and 13
(16%) of 19 on a second repeat biopsy.

McNeal and Bostwick identified PIN
in 82% of prostates studied at autopsy in men with cancer, but they also
identified HGPIN in only 43% of men of similar age who had benign prostatic
hyperplasia (BPH).9 Qian et al found that 86% of 195 whole-mount
radical prostatectomy specimens contained HGPIN, which was usually located
within 2 mm of the cancer.10 The severity and extent of HGPIN was
increased compared with cancer-free prostates.

International

No racial or societal differences in the prevalence of HGPIN or in
its association with prostate cancer have been found.

Mortality/Morbidity

Mortality and morbidity are not directly associated with the
presence of PIN or ASAP. Prostate cancer, which may require therapy, develops in
a significant number of men with HGPIN and in perhaps even more men with ASAP.
Many experts believe that neither HGPIN nor ASAP requires any specific therapy.
Others believe that therapy should be considered, particularly in men with
multiple foci of HGPIN or ASAP. Some evidence indicates that the use of
selective estrogen receptor modulators (SERMs), 5-alpha reductase inhibitors,
and antiandrogens may decrease the risk of cancer.

Race

No racial differences in the frequency of HGPIN or ASAP have been
identified, but racial differences related to the presence of clinically active
prostate cancer have been reported. The highest rate of prostate cancer is in
black males.

Age

Most studies indicate that the risk and extent of HGPIN and ASAP increase
with patient age. However, McNeal and Bostwick reported that this correlation
was not evident in patients with prostate cancer who were older than 50
years.9

Lee et al studied 256 patients who underwent ultrasonography-guided
prostate biopsies and identified 103 patients with cancer and an additional 27
who had PIN and cancer. The mean age of those with PIN was 65 years; the mean
age of those with cancer was 70 years.

Qian et al studied 195 radical prostatectomy specimens and observed that
the volume of HGPIN increased with age.10 In order to determine if
HGPIN alone had the same prognostic significance as HGPIN associated with
adjacent atypical glands, Alsikafi et al studied 485 consecutive patients who
underwent prostate biopsies.11 The overall rate of HGPIN with or
without associated atypical glands was 6.8% (33 patients). Of these patients,
21 (64%) had HGPIN alone and 12 (36%) had HGPIN with adjacent atypical glands.
Subsequent biopsies helped identify the presence of prostate cancer in 3 (14%)
of the patients in whom only HGPIN was found on the initial biopsy, while 9
(75%) patients with adjacent atypical glands were subsequently found to have
cancer.

Clinical

History

Neither high-grade prostatic intraepithelial neoplasia (HGPIN) nor
atypical small acinar proliferation (ASAP) alone causes symptoms; however, they
may be precursors to prostate cancer and are therefore important. Ordinarily, in
patients in whom only a single focus of disease is identified (particularly with
HGPIN), therapy may not be necessary. In patients with multiple areas of HGPIN
or ASAP on the initial or subsequent biopsies, therapy may be considered,
as the risk of cancer in these patients is greatly increased. Prostate
cancer–prevention studies indicate that 5-alpha reductase inhibitors,
antiandrogens, and SERMs may be effective in eliminating these histologic
entities, thus decreasing the risk of prostate cancer.

Neither HGPIN nor
ASAP seems to affect PSA production, meaning that PSA evaluation cannot be used
to monitor the progression of these entities. In addition, they are not readily
detectable with any imaging technology. Only prostate biopsy can be used to
identify these lesions.

HGPIN and cancer share some molecular
alterations, including the loss of heterozygosity at 8p, 10q, and 16q. Studies
in animal models have helped to solidify the association of HGPIN with prostate
cancer. Treatment consisting of testosterone and estradiol in Noble rats
recapitulates the progression from normal histology to cancer. Both low-grade
PIN (LGPIN) and HGPIN can be identified.

The transgenic adenocarcinoma of
mouse prostate (TRAMP) model reproduces the natural history of human prostate
cancer. By expressing an SV40 early gene under prostate-specific control
of the probasin promoter, TRAMP mice display PIN by 6-12 weeks,
well-differentiated cancer by 10-16 weeks, and metastatic disease by 18-24
weeks.

Physical

No physical examination findings reveal the presence of PIN or ASAP.
The prostate may be enlarged secondary to BPH, but this is unrelated to HGPIN.
Areas in the prostate may have palpable nodules, or other areas may indicate
cancer. None of these physical findings suggests the presence of HGPIN or ASAP.
Pathologists can identify this lesion only by microscopically examining
prostatic tissue.

Causes

No known specific risk factors are associated with the development of
HGPIN or ASAP. Environmental and dietary factors have been implicated in the
development of prostate cancer, but whether these factors are associated with
PIN or ASAP formation is unknown.

Epidemiologic studies suggest that the major dietary factor associated
with prostate cancer is fat intake. An additional component is total energy
(caloric) intake (regardless of source). Obesity and a high-fat diet have been
shown to correlate with the development of prostatic cancer, as do genetic and
many other unknown factors.

Differential Diagnoses

Other Problems to Be Considered

Lobular atrophy
Postatrophic hyperplasia
Atypical basal cell
hyperplasia
Cribriform hyperplasia
Radiation-induced
metaplasia
Infarction
Prostatitis
Inflammatory atypia of the benign
epithelium
Cribriform adenocarcinoma
Ductal carcinoma
Urothelial
carcinoma involving prostatic ducts and acini

Workup

Laboratory Studies

No laboratory studies can be used to confirm a diagnosis of high-grade
prostatic intraepithelial neoplasia (HGPIN) or atypical small acinar
proliferation (ASAP).

Serum PSA levels are not affected by HGPIN or ASAP but may be elevated in
the presence of an associated cancer or an inflammatory process.

Imaging Studies

Imaging studies, including standard and color Doppler ultrasonography, CT
scanning, and MRI of the prostate, have not proven beneficial in identifying
the presence of HGPIN or ASAP.

Color Doppler ultrasonography can reveal abnormal areas in the prostate
that have increased vascularity. Some prostate cancers can be identified with
this technique, but areas of inflammation may have the same visual
characteristics. In addition, not all cancers have enough vascularity to
permit identification. The vascular changes caused by HGPIN and ASAP are not
sufficient for identification.

MRI with spectroscopy may reveal areas with biochemical abnormalities
suggestive of cancer, but HGPIN and ASAP are more difficult to find because
they are small and multifocal and are often located at the periphery of a
cancer.

Neither HGPIN nor ASAP can metastasize. These lesions are located only in
the prostate gland.

Other Tests

No routine laboratory tests are used to evaluate for the presence of HGPIN
or ASAP. Once identified, phenotypic biomarkers can be obtained for
experimental purposes. Such studies show that HGPIN is more closely related to
carcinoma than to benign epithelium. Cytoplasmic expression of p160-erb
-b3 and p185-erb -b2 is greater in HGPIN and cancer than in normal or
hyperplastic epithelium.

HGPIN and high-grade cancer are associated with the loss of secretory
markers (eg, PSA cytoskeletal proteins, glycoproteins). These markers have no
specific clinical value in predicting the progression of PIN to cancer but
lend further evidence to the concept that HGPIN is a precursor to
cancer.

Procedures

Prostate biopsy

Biopsy is the definitive method for detecting PIN and early invasive
prostate cancer. Attempts at using imaging studies (eg, ultrasonography,
MRI) have failed to detect PIN or to distinguish it from areas suggestive of
cancer. Transrectal ultrasonography-guided biopsies using the 12-core (or
more) biopsy schemes described in Treatment are most likely to reveal
clinically significant cancers and areas of PIN.

Pathologists have developed criteria for distinguishing HGPIN and ASAP
from benign and malignant conditions and report the presence and extent of
these lesions. The presence of PIN or ASAP may influence therapeutic choices
and management decisions.

Multicentricity and location of HGPIN, ASAP, and prostate cancer

HGPIN, ASAP, and prostate cancer are usually multicentric. Bostwick
and Brawer reported that HGPIN was multicentric in 72% of radical
prostatectomy specimens, which included 63% of those involving a
non–transition zone and 7% of those occurring within the transition
zone.1 Only 2% of the specimens had concomitant single foci in
all zones.

The peripheral zone accounts for 75-80% of all prostate cancers and is
the most common location for HGPIN and ASAP. In a report by Qian et al,
63% of documented PIN was in the peripheral zone, 36% was found in the
peripheral and transition zones, and only 1% was found solely in the
transition zone.10

The transition zone, which is periurethral and the area where BPH
develops, accounts for 20-25% of prostate cancers, and up to 37% of these
patients have HGPIN. Most transition zones that contain PIN and cancer are
found in radical prostatectomy specimens.

This implies that HGPIN and ASAP, as possible precursor lesions to
cancer, may account for most cancers that arise in the transition zone.
Pathologists usually diagnose these cancers based on tissue specimens
obtained during transurethral resection of the prostate or from an adenoma
surgically removed as a result of suspected BPH.

Volume of PIN in prostates

The mean volume of HGPIN or ASAP in prostates with cancer is 1.2-1.32
mL. The volume of HGPIN correlates directly with increasing pathologic
stage, Gleason grade, positive surgical margins, and perineural invasion.

No data demonstrate a correlation between the amount of PIN and the
timing of tumor progression or length of survival.

Continuum from normal to neoplastic prostatic epithelium

A morphologic continuum has been identified that demonstrates the
histologic changes that occur during the transition from normal prostatic
epithelium to early invasive carcinoma. Low-grade PIN (LGPIN) is a
minimal-to-mild dysplasia, whereas HGPIN corresponds with
moderate-to-severe dysplasia and carcinoma in situ. This cancer precursor
state ends when the cells begin to penetrate the basement membrane and
invade the stroma. This invasion is associated with a disruption of the
basal cell layer, which is considered to be evidence for adenocarcinoma.

Although most pathologists recognize the association between HGPIN and
prostate cancer and the higher rate of cancer in patients who harbor
HGPIN, they do not all agree that every lesion is necessarily
premalignant.

Basal cell–specific monoclonal antibodies directed against high
molecular weight keratin are used to identify these HGPIN cells. Normal
prostatic epithelial cells are consistently stained with these antibodies,
showing a continuous, intact, circumferential basal cell layer. Cancer
cells have lost their receptors for these antibodies.

Basal cell disruption affects 56% of patients with HGPIN and is
usually found in glands adjacent to invasive cancer. The degree of
disruption correlates with HGPIN. More than one third of the basal cell
layer is lost in 52% of foci that contain HGPIN.

In persons with HGPIN and in many with low-grade cancer, the basement
membrane that surrounds the prostatic glands remains intact. The
expression of collagenase type 4 in PIN and associated cancer cells is
abnormally high. The presence of collagenase type 4 and other enzymes is
associated with a degradation of the basement membrane, allowing cell
invasion into the stroma. Concurrently, the basal cell layer is
diminished. This seems to occur primarily at sites of glandular
outpouching.

Increased angiogenesis with an increased number of microvessels is
associated with the progression of HGPIN to cancer. The microvessels in
HGPIN are shorter than those in benign epithelium and have irregular
contours and open lumens, an increased number of endothelial cells, and a
greater distance from the basement membrane.

Cell proliferation and apoptosis

Cancer cell growth represents a balance between cell proliferation and
apoptosis, which depends on various factors, including patient age,
nutritional status, hormonal status, and growth factors in the
microenvironment.

Prostate cancer has a relatively slow doubling time compared with
other epithelial cancers. Depending on the tumor grade, doubling times
range from 0.5-5 years. PSA measurements can be used as a surrogate to
evaluate tumor growth. Log-linear growth rates tend to be constant, with a
mean doubling time of 2.4 years in localized cancers and 1.8 years in
metastatic prostate cancer. High Gleason grades (4-5) are associated with
even shorter doubling times.

Immunohistochemical analysis using antibodies against proliferating
cell nuclear antigen and Ki-67 show a mean growth fraction of 8.7-16.3%,
with the most rapid growth located at the advancing edge of the cancer.
The growth fraction is 0.6% in atrophic prostatic glands, 3.2-4% in BPH,
6-9.5% in LGPIN, and 7.9-13% in HGPIN.

Mitotic figures are rare in the epithelium of benign and neoplastic
prostate cells, but mitosis progressively increases during the transition
from benign to PIN to malignancy. Mitotic figures in BPH are found in the
basal cell, with a mean value of 0.002%. In PIN, most of the mitotic
figures are found in the basal cells, with a diminishing number as the
layers reach the luminal surface. In HGPIN, the mean value of mitotic
figures is 0.19% in the basal layer, 0.08% in the intermediate layers, and
0.05% in the superficial layer.

Apoptotic bodies can be found throughout the normal prostatic
epithelium and in the gland lumens. In the transition from BPH to PIN to
cancer, the number of apoptotic bodies progressively increase, with the
greatest number found in the basal cell layer or at the periphery of
malignant glands adjacent to the stroma. The percentage of apoptotic
bodies is 0.26% in BPH, 0.68% in LGPIN, 0.75% in HGPIN, and 0.92-2.1% in
cancer. Mitotic figures do not correlate with apoptotic bodies.

Cytoplasmic expression of BCL2, the oncogene that suppresses
apoptosis, is greater in PIN (100% of cells) and cancer (62% of cells)
than in benign and hyperplastic epithelium. Enhanced expression of
BCL2 seems to play an early role in the progression of normal cells
to cancer cells by allowing cells with genetic abnormalities to escape the
natural apoptotic mechanism.

Morphologic similarities of HGPIN and cancer

Many studies have demonstrated a remarkable similarity between the
nuclear characteristics of prostate cancer cells and HGPIN compared with
those of normal and hyperplastic epithelium.

These include nuclear area, DNA content, chromatin content, chromatin
distribution, nuclear perimeter, nuclear diameter, and nuclear roundness.
Cancer cells and PIN also share nucleolar abnormalities. The results of
these studies further support the concept that a morphologic continuum
from normal to PIN to cancer exists.

Genetic instability in PIN

Studies of nuclear DNA content demonstrate a progressive genetic
instability in the progression from normalcy to PIN and then to cancer.
Montironi et al postulated that 2 successive phases of intraepithelial
neoplasia occur.12 The first is identified in hyperplastic
epithelium and LGPIN and is characterized by DNA duplication without
nuclear division, which results in euploidy. The second is found only in
HGPIN and cancer in which an emergence of aneuploid cells occurs.

Petein et al observed that the mean proliferative index and proportion
of aneuploid cell nuclei in HGPIN were similar to those in cancer but
significantly differed from those found in hyperplastic epithelial cells
and LGPIN.13 Amin et al found a frequency of 32% aneuploidy in
HGPIN and 55% in cancer.14 Others have noted similar findings
and have found that up to 70% of aneuploid cases were associated with
aneuploid invasive cancer, whereas 29% of aneuploid cancer was associated
with aneuploid HGPIN.

Histologic Findings

The description of PIN comes largely through the work of Bostwick
and O'Neil. They have defined this entity and provided the most comprehensive
elucidation of its appearance.

PIN in biopsy samples usually involves
single acini or small clusters of acini. When the entire prostate is available
for analysis, multiple areas of PIN can usually be identified. Acini appear
hyperchromatic because of proliferation, crowding, and irregular spacing of the
inner secretory cells in contrast to the benign acini. The acini are medium
sized or enlarged with rounded contours. Occasionally, a portion of acini shows
changes attributed to PIN. Overlapping nuclei are prominent, and cell borders
are indistinct. On the luminal surface, most cells display cytoplasmic blebs
suggestive of apocrine secretion.

In LGPIN, the epithelium lining ducts
and acini are heaped up, crowded, and irregularly spaced. Nuclear size greatly
varies. Elongated hyperchromatic nuclei and small nucleoli may be present. The
diagnosis of PIN requires a combination of cytologic and architectural features.
Lesions that display some but not all features are considered atypical but not
neoplastic. Many pathologists do not attempt to report LGPIN.

HGPIN is
considered a precursor of prostate cancer. This microscopic entity consists of a
proliferation of epithelial cells with cytologic changes associated with
carcinoma, including nuclear and nucleolar enlargement. HGPIN resembles LGPIN,
but nucleomegaly, cell crowding, and stratification are more pronounced. Nuclear
size is less variable because most nuclei are enlarged. The presence of
prominent nucleoli, often multiple, is typical of HGPIN.

At the periphery
of PIN, the basal cell layer is usually inconspicuous and may be difficult to
visualize on routine light microscopy. Discontinuity of the basal cell layer is
a distinctive finding in about half of acini with HGPIN and often requires
immunohistochemical studies.

As mentioned above, HGPIN has 4 main
architectural patterns: tufting, micropapillary, cribriform, and flat. These
patterns often merge with each other. Other than diagnostic utility, these
architectural patterns have no known clinical significance.

HGPIN and
prostate cancer are almost always multifocal within the prostate. PIN spreads
through prostatic ducts in several different methods similar to cancer.
Neoplastic cells may replace the normal luminal secretory epithelium without
disrupting the basal cell layer and basement membrane. Foci of HGPIN are often
indistinguishable from ductal spread of carcinoma on routine light microscopy.
In another pattern, direct invasion through the ductal or acinar wall occurs,
with disruption of the basal cell layer. In a third pattern, neoplastic cells
invaginate between the basal cell layers, a finding that is quite rare. Early
invasive carcinoma occurs at sites of acinar outpouching and basal cell
disruption.

Treatment

Medical Care

The association of high-grade prostatic intraepithelial neoplasia
(HGPIN) and atypical small acinar proliferation (ASAP) with prostate cancer
makes these histologic findings clinically significant. HGPIN has been
identified in up to 0.7-20% (average, 4.26%) of patients undergoing needle
biopsies of the prostate, but the frequency is difficult to determine in the
clinical setting because many pathologists do not report its presence.

In
a series of 330 biopsies in men older than 50 years, HGPIN and cancer were
identified in 17 (5.2%) and 58 (15.8%), respectively. Again, pathologists
usually report only HGPIN or cancer.

The presence of HGPIN or ASAP in
multiple areas has such a high predictive value for prostate adenocarcinoma that
its presence alerts the pathologist to search for any areas in the biopsy sample
that might harbor carcinoma. The clinician is also alerted because these
patients must be carefully monitored, and additional biopsies must be collected,
if clinically indicated.

Davidson et al found cancer in 35% of subsequent
biopsy samples in men who had HGPIN and 13% of subsequent biopsy samples in men
without PIN.15 When much of the data on PIN were collected, the
standard biopsy protocol involved obtaining 6 sextant biopsies. The large number
of false-negative results induced a review of this protocol, and the minimum
number of biopsy cores is currently 12, with additional cores taken depending on
the size of the prostate. Additional cores are obtained from the lateral edges
and anterior portion of the prostate and have raised the finding of cancer from
20% to 40%. This technique change has also increased the number of patients in
whom HGPIN is found and in whom prostate cancer is subsequently
found.

HGPIN, patient age, and serum PSA levels are significant
predictors of cancer. The risk of cancer in patients with PIN or ASAP is 15
times that in patients without these entities. The predictive value for cancer
reportedly ranges from 38-100%. Although PIN and ASAP are not considered to be
cancer and do not require therapy, careful follow-up care by a urologist is
necessary. Additional prostate biopsies at 6-month intervals for 2 years (using
the new biopsy protocol) should reveal the presence of any significant cancer. A
patient with a solitary focus of HGPIN who has undergone adequate biopsy with 12
or more cores does not require further biopsies. The PSA level and rectal
prostate examination findings can dictate the need for additional
biopsies.

Prostate biopsy is the only method for identifying the presence
of HGPIN or ASAP and for diagnosing coexisting cancer. HGPIN and ASAP have a
minimal influence on PSA levels, but patients with an elevated PSA level related
to prostate size or those with a rapidly rising PSA level should undergo
follow-up biopsies at 3 or 6 months.

The extent and prevalence of HGPIN in patients treated with androgen
ablation therapy is markedly decreased compared with that in untreated
patients. This decrease is associated with epithelial hyperplasia, cytoplasmic
clearing, and glandular atrophy with a decreased glands-to-stroma ratio. This
suggests that the dysplastic prostate epithelium is hormone-sensitive. In
normal prostate epithelium, luminal secretory cells are more sensitive to the
effects of androgen deprivation than basal cells. HGPIN exhibits this same
sensitivity. The loss of normal, hyperplastic, dysplastic, and cancer cells in
the absence of androgens is mediated by the induction of apoptosis.

In the absence of carcinoma, a finding of HGPIN or ASAP in a biopsy
specimen does not necessarily require further investigation or therapy. The
presence of HGPIN or ASAP alerts a urologist that cancer may be present, which
could be missed in a biopsy sample. Patients with HGPIN or ASAP are at higher
risk for developing a malignancy, although they are not treated until cancer
is diagnosed. Even under this circumstance, therapy may be withheld in some
patients if the cancer is low grade and apparently low volume.

HGPIN and ASAP represent unstable epithelia that may progress to prostate
cancer, although other precursor abnormalities are also likely to be present.
PIN is associated with progressive abnormalities of phenotype and genotype
that represent a continuum between normal prostatic epithelium and cancer. De
Marzo et al used the term proliferative inflammatory atrophy to describe a
group of lesions induced by environmental carcinogens.3 The
presence of HGPIN indicates that abnormalities of cell differentiation and
regulatory control have already started, but they may be reversible at this
stage.

If the genetic alterations associated with HGPIN continue, a progressive
loss of some markers of secretory differentiation occurs, which may include
PSA production, secretory proteins, cytoskeletal proteins, glycoproteins, and
neuroendocrine cells. In contrast, the levels of c-erb -b2 oncoprotein,
BCL2, epidermal growth factor, epidermal growth factor receptor, type 4
collagenase, Lewis Y antigen, transforming growth factor–alpha, apoptotic
bodies, proliferating cell nuclear antigen expression, aneuploidy and various
genetic abnormalities, and microvessel density progressively increase.

HGPIN and ASAP are important because of their association with prostatic
carcinoma. HGPIN and ASAP may remain stable for years in many patients,
regress in some, or progress to invasive cancer in a significant number.
Urologists depend on pathologists to recognize these entities and to
distinguish them from other lesions that may appear similar. Low-grade PIN
(LGPIN) is believed to have clinical outcomes that are different from those of
HGPIN. Most cases of LGPIN do not progress, and follow-up care in patients
with LGPIN is the same as in patients in whom PIN has not been identified.
Most pathologists no longer report the presence of LGPIN.

Surgical Care

Because PIN does not require therapy, surgical procedures are
unnecessary.

Consultations

Confirming a diagnosis of HGPIN, ASAP, or prostate cancer may be
difficult. Review of the slides by another pathologist is beneficial if the
diagnosis is unclear. These lesions may be difficult to diagnose in patients
with chronic or acute inflammation or in those who have received radiation
therapy.

Diet

Dietary factors have been implicated in the development of prostate
cancer. Patients are advised to have a diet low in fat, particularly animal fat,
and high in fruits, vegetables, and fiber. Patients should avoid taking in more
calories than they expend. Whether dietary factors are associated with the
development or management of HGPIN or ASAP is not known.

For more information, See Prostate Cancer: Nutrition.

Medication

Drug therapy is ordinarily not recommended for patients with
high-grade prostatic intraepithelial neoplasia (HGPIN) or atypical small acinar
proliferation (ASAP). In patients with multiple lesions with findings that
persist on repeat biopsy, therapy can be considered. Treatment of HGPIN and ASAP
with 5-alpha reductase inhibitors, antiandrogens, or SERMs has been advocated as
a form of cancer prevention, although the effectiveness of this approach is
unclear. These therapies can reverse HGPIN and ASAP, possibly reducing the risk
of prostate cancer.

For example, toremifene citrate (Acapodene) is a
nonsteroidal SERM that is currently used to treat breast cancer in women. In a
multicenter, double-blind study, 514 men with HGPIN and no cancer (as determined
with prestudy prostatic biopsy results) were randomized to receive either
placebo or various doses of toremifene. All patients then underwent subsequent
biopsies at 6 and 12 months.

The incidence of prostate cancer development in patients who received
toremifene 20 mg for 12 months was 48% less than in the placebo group. Those in
whom prostate cancer did develop had tumor grades that were similar to those in
the placebo group. The medication was well-tolerated, with similar side-effect
profiles between the two groups. Further studies and clinical trials are pending
to determine if toremifene is truly safe and effective in reducing the eventual
development of prostate cancer in patients with HGPIN or ASAP.

Yamauchi
et al used an animal model to investigate the chemopreventive effects of
bicalutamide on prostate cancer and PIN.16 They found that the drug
significantly suppressed cancer cells but that it did not suppress
HGPIN.

Patients with prostate cancer may be treated with surgery,
radiation therapy, cryosurgery, or androgen ablation therapy, depending on the
status of the disease. Drugs used for treating prostate cancer include
luteinizing hormone-releasing hormone agonists or antagonists and antiandrogens.
Patients with metastatic cancer in whom these medications do not elicit a
response may benefit from antineoplastic agents.

Follow-up

Further Outpatient Care

When high-grade prostatic intraepithelial neoplasia (HGPIN) or atypical
small acinar proliferation (ASAP) has been identified, follow-up care is
essential. No clearly established protocol has been established for managing
either condition. A part of the problem relates to the amount of HGPIN or ASAP
that is present. For example, if HGPIN or ASAP is found in only a 1 of 10 or
more biopsy cores, a more limited follow-up protocol would be reasonable. If 6
of 10 cores demonstrate HGPIN or ASAP, a more aggressive program would be
appropriate. Repeat prostate biopsies are generally recommended at 6-month
intervals for 2 years. If the degree of PIN or ASAP is low, , no additional
biopsies would be necessary if the follow-up biopsy finding at 6 months is
negative.

Prostate cancer has been found in 36% of patients following the second
biopsy (ie, the first repeat biopsy), particularly in men with multiple
positive cores.

Moore et al assert that no additional biopsies are necessary if the
first repeat biopsy shows no HGPIN or ASAP, but this is PIN
volume–related.8 Neither PIN nor ASAP alone changes the PSA
level. A continuously rising PSA level that is doubling at 12 months or less
would prompt the need for prostate biopsies, regardless of the presence of
PIN or ASAP.

The number of biopsies necessary correlates with the size of the prostate
and to the presence of palpable lesions. Current biopsy techniques include
applying local anesthesia by injecting lidocaine around the base of the
prostate and/or instilling lidocaine gel into the rectum.

Most urologists obtain at least 8 cores of tissue; if the prostate
volume is approximately 40 mL, 12 cores are obtained. The larger the
prostate and the higher the level of suspicion, the more cores obtained.

PIN and ASAP tend to arise in the peripheral zone of the prostate, which
is located on the posterior surface of the prostate, arching anteriorly on
each side. Ultrasonographic studies help to understand the anatomy and to
develop a reasonable biopsy strategy for each patient. Color Doppler and MRI
are used to visualize the prostate, but they do not reveal PIN or ASAP and
often cannot be used to distinguish cancer from areas of
inflammation.

Inpatient & Outpatient Medications

Antibiotics are prescribed on the day of a prostate biopsy and, often, for
the following day.

Most authorities do not recommend treating patients with a single focus of
HGPIN. ASAP represents a potentially more serious situation; if ASAP is
confirmed on subsequent biopsy, therapy should be considered. Most urologists
do not treat these conditions, whereas others have advocated the use of
5-alpha reductase inhibitors, anti-inflammatory agents, SERMs, and dietary
supplements (eg, selenium, lycopene). Few data have been collected on the use
of dietary measures to manage these patients.

If HGPIN is present on only a single core, the only course of action
that seems reasonable is to observe the patient at 6-month intervals with
PSA measurements and digital rectal examination.

If multiple biopsy cores demonstrate HGPIN, a repeat biopsy at 6 months
is recommended. If multiple cores of HGPIN are still present (without
cancer), a biopsy should be repeated in another 6 months. If the findings
persist, some type of therapy may be considered.

The finding of ASAP in one or more biopsy samples necessitates a
follow-up biopsy in 6 months. Repeated findings of ASAP may encourage the
urologist to initiate therapy.

Deterrence/Prevention

No known measures that prevent the development of HGPIN or ASAP have
been identified. Numerous agents, including finasteride, bicalutamide, selenium,
vitamin E, soy isoflavonoids, and toremifene, have been studied to determine
their ability to eradicate HGPIN.

Complications

The only potential complication of HGPIN or ASAP is the development
of prostate adenocarcinoma.

Prognosis

The prognostic significance of HGPIN and ASAP is related to possible
development of prostate cancer. HGPIN and ASAP are important because they are
frequently associated with cancer, although their presence does not
necessarily imply that prostate cancer is inevitable. The grade and stage of
prostate cancer has prognostic significance, but the presence of HGPIN or ASAP
does not alter this prognosis.

The importance of recognizing HGPIN and ASAP relates to their association
with prostatic carcinoma. HGPIN may remain stable for years in many patients,
regress in some, or progress to invasive cancer.

Patient Education

Patients with HGPIN or ASAP not associated with an existing prostate
cancer should be informed about the need for surveillance because they are at
an increased risk for developing prostate cancer. Patients should be informed
that neither HGPIN nor ASAP affects PSA levels.

Regular PSA measurements and physical examinations should be performed
every 6 months. Patients with HGPIN who have only a single biopsy core
demonstrating HGPIN do not need additional biopsies. Patients with multiple
cores of HGPIN or even one biopsy core positive for ASAP should have repeat
biopsies at 6-month intervals for at least 2 years.

Miscellaneous

Medicolegal Pitfalls

Failing to diagnose high-grade prostatic intraepithelial neoplasia (HGPIN)
or atypical small acinar proliferation (ASAP) is not nearly as important as
failing to diagnose prostate cancer. However, a physician who fails to
carefully monitor a patient with PIN or ASAP and to inform him that he may be
at increased risk for developing prostate cancer is not serving the best
interests of the patient.

The presence of HGPIN or ASAP should alert the physician to the
possibility of an existing cancer and to the patient’s heightened risk of
developing prostate cancer in the future.

Special Concerns

HGPIN is generally diagnosed without difficulty. ASAP includes various
microscopic entities such as lobular atrophy, postatrophic hyperplasia,
atypical basal cell hyperplasia, atypical adenomatous hyperplasia, cribriform
hyperplasia, radiation-induced metaplasia, infarction, and prostatitis.
Inflammatory atypia of the benign epithelium is the most frequently
encountered cellular change that mimics HGPIN. In the presence of acute or
chronic inflammation, the diagnosis of HGPIN or ASAP can be very difficult to
confirm, and non-PIN lesions show architectural and cytologic alterations,
including cytologic abnormalities, that can be confused with HGPIN.

HGPIN and ASAP are difficult, if not impossible, to recognize following
radiation therapy. The cytologic changes caused by radiation therapy have many
similarities to those associated with HGPIN. Nevertheless, Arakawa et al found
that the frequency of HGPIN in radical prostatectomy specimens obtained
following radiation therapy was similar to the rate found in nonradiated
prostatectomy specimens.17

Cribriform adenocarcinoma, ductal carcinoma, and urothelial carcinoma
involving prostatic ducts and acini are malignant lesions that may also be
confused with HGPIN.

ASAP is considered to be precancerous and has a greater association with
prostate cancer than HGPIN. ASAP is characterized by localized proliferation
of small acini that may be confused with cancer. These lesions are usually
found in intimate association with nodular hyperplasia in the transition zone,
often at the periphery of a nodule. Cytologic and histologic features
distinguish ASAP from PIN, but differentiating ASAP from cancer may be very
difficult.

Despite the apparent survival advantage of early diagnosis conferred by
PSA screening, a recent U.S. Preventive Services Task Force statement
recommends against screening for prostate cancer in men aged 75 years or
older. The statement also concludes that, currently, the balance of benefits
versus drawbacks of prostate cancer screening in men younger than age 75 years
cannot be assessed because of insufficient evidence.18

References

Bostwick DG, Brawer MK. Prostatic intra-epithelial neoplasia and early
invasion in prostate cancer. Cancer. Feb
15 1987;59(4):788-94. [Medline].

Bostwick DG, Amin MB, Dundore P, Marsh W, Schultz DS. Architectural
patterns of high-grade prostatic intraepithelial neoplasia. Hum
Pathol. Mar 1993;24(3):298-310. [Medline].

De Marzo AM, Nakai Y, Nelson WG. Inflammation, atrophy, and prostate
carcinogenesis. Urol
Oncol. Sep-Oct 2007;25(5):398-400. [Medline].

Orozco R, O'Dowd G, Kunnel B, Miller MC, Veltri RW. Observations on
pathology trends in 62,537 prostate biopsies obtained from urology private
practices in the United
States. Urology. Feb 1998;51(2):186-95. [Medline].

Novis DA, Zarbo RJ, Valenstein PA. Diagnostic uncertainty expressed in
prostate needle biopsies. A College of American Pathologists Q-probes Study of
15,753 prostate needle biopsies in 332 institutions. Arch Pathol Lab
Med. Aug 1999;123(8):687-92. [Medline].

Borboroglu PG, Comer SW, Riffenburgh RH, Amling CL. Extensive repeat
transrectal ultrasound guided prostate biopsy in patients with previous benign
sextant biopsies. J
Urol. Jan 2000;163(1):158-62. [Medline].

O'dowd GJ, Miller MC, Orozco R, Veltri RW. Analysis of repeated biopsy
results within 1 year after a noncancer
diagnosis. Urology. Apr 2000;55(4):553-9. [Medline].

Moore CK, Karikehalli S, Nazeer T, Fisher HA, Kaufman RP Jr, Mian
BM. Prognostic significance of high grade prostatic intraepithelial
neoplasia and atypical small acinar proliferation in the contemporary
era. J Urol. Jan 2005;173(1):70-2. [Medline].

McNeal JE, Bostwick DG. Intraductal dysplasia: a premalignant lesion
of the prostate. Hum
Pathol. Jan 1986;17(1):64-71. [Medline].

Qian J, Wollan P, Bostwick DG. The extent and multicentricity of
high-grade prostatic intraepithelial neoplasia in clinically localized
prostatic adenocarcinoma. Hum
Pathol. Feb 1997;28(2):143-8. [Medline].

Alsikafi NF, Brendler CB, Gerber GS, Yang XJ. High-grade prostatic
intraepithelial neoplasia with adjacent atypia is associated with a higher
incidence of cancer on subsequent needle biopsy than high-grade prostatic
intraepithelial neoplasia
alone. Urology. Feb 2001;57(2):296-300. [Medline].

Montironi R, Mazzucchelli R, Scarpelli M. Precancerous lesions and
conditions of the prostate: from morphological and biological characterization
to chemoprevention. Ann N Y Acad
Sci. Jun 2002;963:169-84. [Medline].

Petein M, Michel P, van Velthoven R, Pasteels JL, Brawer MK, Davis JR, et
al. Morphonuclear relationship between prostatic intraepithelial
neoplasia and cancers as assessed by digital cell image analysis. Am J
Clin Pathol. Nov 1991;96(5):628-34. [Medline].

Amin MB, Ro JY, Ayala AG. Putative precursor lesions of prostatic
adenocarcinoma: fact or fiction?. Mod
Pathol. Jul 1993;6(4):476-83. [Medline].

Davidson D, Bostwick DG, Qian J, Wollan PC, Oesterling JE, Rudders RA, et
al. Prostatic intraepithelial neoplasia is a risk factor for
adenocarcinoma: predictive accuracy in needle biopsies. J
Urol. Oct 1995;154(4):1295-9. [Medline].

Yamauchi A, Kawai K, Tsukamoto S, Ideyama Y, Shirai T, Akaza
H. Persistence of prostatic intraepithelial neoplasia after effective
chemoprevention of microscopic prostate cancer with antiandrogen in a rat
model. J Urol. Jan 2006;175(1):348-52. [Medline].

Arakawa A, Song S, Scardino PT, Wheeler TM. High grade prostatic
intraepithelial neoplasia in prostates removed following irradiation failure
in the treatment of prostatic adenocarcinoma. Pathol Res
Pract. Sep 1995;191(9):868-72. [Medline].

U.S. Preventive Services Task Force. Screening for prostate cancer:
U.S. Preventive Services Task Force recommendation statement. Ann
Intern Med. Aug 5 2008;149(3):185-91. [Medline].

Akhavan A, Keith JD, Bastacky SI, Cai C, Wang Y, Nelson JB. 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. BJU
Int. Apr 2007;99(4):765-9. [Medline].

Allam CK, Bostwick DG, Hayes JA, Upton MP, Wade GG, Domanowski GF, et
al. Interobserver variability in the diagnosis of high-grade prostatic
intraepithelial neoplasia and adenocarcinoma. Mod
Pathol. Jul 1996;9(7):742-51. [Medline].

Babaian RJ, Toi A, Kamoi K, Troncoso P, Sweet J, Evans R, et al. A
comparative analysis of sextant and an extended 11-core multisite directed
biopsy strategy. J Urol. Jan 2000;163(1):152-7. [Medline].

Bigler SA, Deering RE, Brawer MK. Comparison of microscopic
vascularity in benign and malignant prostate tissue. Hum
Pathol. Feb 1993;24(2):220-6. [Medline].

Bishara T, Ramnani DM, Epstein JI. High-grade prostatic
intraepithelial neoplasia on needle biopsy: risk of cancer on repeat biopsy
related to number of involved cores and morphologic pattern. Am J Surg
Pathol. May 2004;28(5):629-33. [Medline].

Bostwick DG. c-erbB-2 oncogene expression in prostatic intraepithelial
neoplasia: mounting evidence for a precursor role. J Natl Cancer
Inst. Aug 3 1994;86(15):1108-10. [Medline].

Bostwick DG. High grade intraepithelial neoplasia. The most likely
precursor of prostate cancer. Cancer. 1995;75:1823-1836.

Bostwick DG. Premalignant lesions of the prostate. Semin Diagn
Pathol. Aug 1988;5(3):240-53. [Medline].

Bostwick DG. Prospective origins of prostate carcinoma. Prostatic
intraepithelial neoplasia and atypical adenomatous
hyperplasia. Cancer. Jul 15 1996;78(2):330-6. [Medline].

Bostwick DG. Prostatic intraepithelial neoplasia (PIN): current
concepts. J Cell Biochem Suppl. 1992;16H:10-9. [Medline].

Bostwick DG, Algaba F, Amin MB, Ayala A, Eble J, Goldstein N, et
al. Consensus statement on terminology: recommendation to use atypical
adenomatous hyperplasia in place of adenosis of the prostate. Am J
Surg Pathol. Oct 1994;18(10):1069-70. [Medline].

Bostwick DG, Dousa MK, Crawford BG, Wollan PC. Neuroendocrine
differentiation in prostatic intraepithelial neoplasia and
adenocarcinoma. Am J Surg
Pathol. Dec 1994;18(12):1240-6. [Medline].

Bostwick DG, Neumann R, Qian J, Cheng L. Reversibility of prostatic
intraepithelial neoplasia: implications for chemoprevention. Eur
Urol. 1999;35(5-6):492-5. [Medline].

Bostwick DG, Pacelli A, Lopez-Beltran A. Molecular biology of
prostatic intraepithelial
neoplasia. Prostate. Aug 1996;29(2):117-34. [Medline].

Bostwick DG, Qian J, Frankel K. The incidence of high grade prostatic
intraepithelial neoplasia in needle biopsies. J
Urol. Nov 1995;154(5):1791-4. [Medline].

Brand TC, Thibault GP, Basler JW. Dealing with non-cancerous findings
on prostate biopsy. Curr Urol
Rep. May 2006;7(3):186-92. [Medline].

Brawer MK, Bigler SA, Sohlberg OE, Nagle RB, Lange PH. Significance of
prostatic intraepithelial neoplasia on prostate needle
biopsy. Urology. Aug 1991;38(2):103-7. [Medline].

Brimo F, Vollmer RT, Corcos J, Humphrey PA, Bismar TA. Outcome for
repeated biopsy of the prostate: roles of serum PSA, small atypical glands,
and prostatic intraepithelial neoplasia. Am J Clin
Pathol. Oct 2007;128(4):648-51. [Medline].

Chappell B, McLoughlin J. Technical considerations when obtaining and
interpreting prostatic biopsies from men with suspicion of early prostate
cancer: part 2. BJU Int. Jun 2005;95(8):1141-5. [Medline].

Che M, Sakr W, Grignon D. Pathologic features the urologist should
expect on a prostate biopsy. Urol
Oncol. Mar-Apr 2003;21(2):153-61. [Medline].

Dawson DM, Lawrence EG, MacLennan GT, Amini SB, Kung HJ, Robinson D, et
al. Altered expression of RET proto-oncogene product in prostatic
intraepithelial neoplasia and prostate cancer. J Natl Cancer
Inst. Apr 1 1998;90(7):519-23. [Medline].

de la Torre M, Häggman M, Brändstedt S, Busch C. Prostatic
intraepithelial neoplasia and invasive carcinoma in total prostatectomy
specimens: distribution, volumes and DNA ploidy. Br J
Urol. Aug 1993;72(2):207-13. [Medline].

Epstein JI, Grignon DJ, Humphrey PA, McNeal JE, Sesterhenn IA, Troncoso P,
et al. Interobserver reproducibility in the diagnosis of prostatic
intraepithelial neoplasia. Am J Surg
Pathol. Aug 1995;19(8):873-86. [Medline].

Epstein JI, Herawi M. Prostate needle biopsies containing prostatic
intraepithelial neoplasia or atypical foci suspicious for carcinoma:
implications for patient care. J Urol. Mar 2006;175(3 Pt
1):820-34. [Medline].

Epstein JI, Potter SR. The pathological interpretation and
significance of prostate needle biopsy findings: implications and current
controversies. J Urol. Aug 2001;166(2):402-10. [Medline].

Ferguson J, Zincke H, Ellison E, Bergstrahl E, Bostwick DG. Decrease
of prostatic intraepithelial neoplasia following androgen deprivation therapy
in patients with stage T3 carcinoma treated by radical
prostatectomy. Urology. Jul 1994;44(1):91-5. [Medline].

Flury SC, Galgano MT, Mills SE, Smolkin ME, Theodorescu D. Atypical
small acinar proliferation: biopsy artefact or distinct pathological
entity?. BJU Int. Apr 2007;99(4):780-5. [Medline].

Giannulis I, Montironi R, Galluzzi CM, de Nictolis M, Diamanti
L. Frequency and location of mitoses in prostatic intraepithelial
neoplasia (PIN). Anticancer
Res. Nov-Dec 1993;13(6B):2447-51. [Medline].

Gore JL, Shariat SF, Miles BJ, Kadmon D, Jiang N, Wheeler TM, et
al. Optimal combinations of systematic sextant and laterally directed
biopsies for the detection of prostate cancer. J
Urol. May 2001;165(5):1554-9. [Medline].

Graham SD Jr, Bostwick DG, Hoisaeter A, Abrahamsson P, Algaba F, di
Sant'Agnese A, et al. Report of the Committee on Staging and
Pathology. Cancer. Jul 1 1992;70(1
Suppl):359-61. [Medline].

Häggman MJ, Adolfsson J, Khoury S, Montie JE, Norlén J. Clinical
management of premalignant lesions of the prostate. WHO Collaborative Project
and Consensus Conference on Public Health and Clinical Significance of
Premalignant Alterations in the Genitourinary Tract. Scand J Urol
Nephrol Suppl. 2000;(205):44-9. [Medline].

Izawa JI, Lega I, Downey D, Chin JL, Luke PP. Do all patients with
high-grade prostatic intraepithelial neoplasia on initial prostatic biopsy
eventually progress to clinical prostate cancer?. BJU
Int. Aug 2005;96(3):320-3. [Medline].

Joniau S, Goeman L, Roskams T, Lerut E, Oyen R, Van Poppel H. Effect
of nutritional supplement challenge in patients with isolated high-grade
prostatic intraepithelial
neoplasia. Urology. Jun 2007;69(6):1102-6. [Medline].

Kang TY, Nichols P, Skinner E, Groshen S, Valin G, Ye W, et
al. Functional heterogeneity of prostatic intraepithelial neoplasia: the
duration of hormonal therapy influences the response. BJU
Int. May 2007;99(5):1024-7. [Medline].

Keetch DW, Humphrey P, Stahl D, Smith DS, Catalona WJ. Morphometric
analysis and clinical followup of isolated prostatic intraepithelial neoplasia
in needle biopsy of the prostate. J Urol. Aug 1995;154(2
Pt 1):347-51. [Medline].

Kronz JD, Shaikh AA, Epstein JI. High-grade prostatic intraepithelial
neoplasia with adjacent small atypical glands on prostate biopsy. Hum
Pathol. Apr 2001;32(4):389-95. [Medline].

Lefkowitz GK, Sidhu GS, Torre P, Lepor H, Taneja SS. Is repeat
prostate biopsy for high-grade prostatic intraepithelial neoplasia necessary
after routine 12-core
sampling?. Urology. Dec 2001;58(6):999-1003. [Medline].

Li Z, Szabolcs M, Terwilliger JD, Efstratiadis A. Prostatic
intraepithelial neoplasia and adenocarcinoma in mice expressing a probasin-Neu
oncogenic
transgene. Carcinogenesis. May 2006;27(5):1054-67. [Medline].

López JI. Prostate adenocarcinoma detected after high-grade prostatic
intraepithelial neoplasia or atypical small acinar proliferation. BJU
Int. Dec 2007;100(6):1272-6. [Medline].

Mallén E, Gil P, Sancho C, Jesús Gil M, Allepuz C, Borque A, et
al. Atypical small acinar proliferation: review of a series of 64
patients. Scand J Urol Nephrol. 2006;40(4):272-5. [Medline].

Maygarden SJ, Strom S, Ware JL. Localization of epidermal growth
factor receptor by immunohistochemical methods in human prostatic carcinoma,
prostatic intraepithelial neoplasia, and benign hyperplasia. Arch
Pathol Lab Med. Mar 1992;116(3):269-73. [Medline].

McNeal JE, Alroy J, Leav I, Redwine EA, Freiha FS, Stamey
TA. Immunohistochemical evidence for impaired cell differentiation in the
premalignant phase of prostate carcinogenesis. Am J Clin
Pathol. Jul 1988;90(1):23-32. [Medline].

Meng MV, Shinohara K, Grossfeld GD. Significance of high-grade
prostatic intraepithelial neoplasia on prostate biopsy. Urol
Oncol. Mar-Apr 2003;21(2):145-51. [Medline].

Montironi R, Braccischi A, Matera G, Scarpelli M, Pisani
E. Quantitation of the prostatic intra-epithelial neoplasia. Analysis of
the nucleolar size, number and location. Pathol Res
Pract. Mar 1991;187(2-3):307-14. [Medline].

Montironi R, Mazzucchelli R, Lopez-Beltran A, Cheng L, Scarpelli
M. Mechanisms of disease: high-grade prostatic intraepithelial neoplasia
and other proposed preneoplastic lesions in the prostate. Nat Clin
Pract Urol. Jun 2007;4(6):321-32. [Medline].

Myers RB, Srivastava S, Oelschlager DK, Grizzle WE. Expression of
p160erbB-3 and p185erbB-2 in prostatic intraepithelial neoplasia and prostatic
adenocarcinoma. J Natl Cancer Inst. Aug
3 1994;86(15):1140-5. [Medline].

Nagle RB, Brawer MK, Kittelson J, Clark V. Phenotypic relationships of
prostatic intraepithelial neoplasia to invasive prostatic
carcinoma. Am J Pathol. Jan 1991;138(1):119-28. [Medline].

Netto GJ, Epstein JI. Widespread high-grade prostatic intraepithelial
neoplasia on prostatic needle biopsy: a significant likelihood of subsequently
diagnosed adenocarcinoma. Am J Surg
Pathol. Sep 2006;30(9):1184-8. [Medline].

Pierorazio PM, Lambert SM, Matsukhani M, Sprenkle PC, McCann TR, Katz AE,
et al. High-grade prostatic intraepithelial neoplasia is an independent
predictor of outcome after radical prostatectomy. BJU
Int. Nov 2007;100(5):1066-70. [Medline].

Postma R, Schröder FH, van der Kwast TH. Atrophy in prostate needle
biopsy cores and its relationship to prostate cancer incidence in screened
men. Urology. Apr 2005;65(4):745-9. [Medline].

Presti JC Jr. Prostate biopsy strategies. Nat Clin Pract
Urol. Sep 2007;4(9):505-11. [Medline].

Qian J, Jenkins RB, Bostwick DG. Genetic and chromosomal alterations
in prostatic intraepithelial neoplasia and carcinoma detected by fluorescence
in situ hybridization. Eur Urol. 1999;35(5-6):479-83. [Medline].

Raghow S, Hooshdaran MZ, Katiyar S, Steiner MS. Toremifene prevents
prostate cancer in the transgenic adenocarcinoma of mouse prostate
model. Cancer Res. Mar 1 2002;62(5):1370-6. [Medline].

Ramos CG, Carvahal GF, Mager DE, Haberer B, Catalona WJ. The effect of
high grade prostatic intraepithelial neoplasia on serum total and percentage
of free prostate specific antigen levels. J
Urol. Nov 1999;162(5):1587-90. [Medline].

Reynolds T. Trials examine intraepithelial neoplasia as a marker for
cancer. J Natl Cancer Inst. Feb
5 2003;95(3):182-4. [Medline].

Ronnett BM, Carmichael MJ, Carter HB, Epstein JI. Does high grade
prostatic intraepithelial neoplasia result in elevated serum prostate specific
antigen levels?. J Urol. Aug 1993;150(2 Pt
1):386-9. [Medline].

Sakr WA. High-grade prostatic intraepithelial neoplasia: additional
links to a potentially more aggressive prostate cancer?. J Natl Cancer
Inst. Apr 1 1998;90(7):486-7. [Medline].

Sakr WA. Prostatic intraepithelial neoplasia: A marker for high-risk
groups and a potential target for chemoprevention. Eur
Urol. 1999;35(5-6):474-8. [Medline].

Sakr WA, Grignon DJ, Haas GP, Schomer KL, Heilbrun LK, Cassin BJ, et
al. Epidemiology of high grade prostatic intraepithelial
neoplasia. Pathol Res
Pract. Sep 1995;191(9):838-41. [Medline].

Sakr WA, Haas GP, Cassin BF, Pontes JE, Crissman JD. The frequency of
carcinoma and intraepithelial neoplasia of the prostate in young male
patients. J Urol. Aug 1993;150(2 Pt 1):379-85. [Medline].

San Francisco IF, Olumi AF, Kao J, Rosen S, DeWolf WC. Clinical
management of prostatic intraepithelial neoplasia as diagnosed by extended
needle biopsies. BJU Int. Mar 2003;91(4):350-4. [Medline].

Scattoni V, Montironi R, Mazzucchelli R, Freschi M, Nava L, Losa A, et
al. Pathological changes of high-grade prostatic intraepithelial
neoplasia and prostate cancer after monotherapy with bicalutamide 150
mg. BJU Int. Jul 2006;98(1):54-8. [Medline].

Schlesinger C, Bostwick DG, Iczkowski KA. High-grade prostatic
intraepithelial neoplasia and atypical small acinar proliferation: predictive
value for cancer in current practice. Am J Surg
Pathol. Sep 2005;29(9):1201-7. [Medline].

Schoenfield L, Jones JS, Zippe CD, Reuther AM, Klein E, Zhou M, et
al. The incidence of high-grade prostatic intraepithelial neoplasia and
atypical glands suspicious for carcinoma on first-time saturation needle
biopsy, and the subsequent risk of cancer. BJU
Int. Apr 2007;99(4):770-4. [Medline].

Sofikerim M, Tatlisen A, Karacagil M. Do all patients with high-grade
prostatic intraepithelial neoplasia on initial prostatic biopsy eventually
progress to clinical prostate cancer?. BJU
Int. Apr 2006;97(4):869-70. [Medline].

Steiner MS, Pound CR. Phase IIA clinical trial to test the efficacy
and safety of Toremifene in men with high-grade prostatic intraepithelial
neoplasia. Clin Prostate
Cancer. Jun 2003;2(1):24-31. [Medline].

Steiner MS, Raghow S. Antiestrogens and selective estrogen receptor
modulators reduce prostate cancer risk. World J
Urol. May 2003;21(1):31-6. [Medline].

Weinstein MH, Epstein JI. Significance of high-grade prostatic
intraepithelial neoplasia on needle biopsy. Hum
Pathol. Jun 1993;24(6):624-9. [Medline].

Yamamoto S, Ito T, Aizawa T, Miki M, Furusato M. The possibility of
'de novo' cancer in the prostate. Int J
Urol. Apr 2005;12(4):361-4. [Medline].

Keywords

prostatic intraepithelial neoplasia, prostate cancer, prostatic
adenocarcinoma, prostate adenocarcinoma, PIN, high-grade prostatic
intraepithelial neoplasia, low-grade prostatic intraepithelial neoplasia,
high-grade PIN, HGPIN, low-grade PIN, LGPIN, atypical small acinar
proliferation, ASAP, intraductal hyperplasia, prostatic hyperplasia with
malignant change, precursor lesions, large acinar atypical hyperplasia, marked
atypia, ductal-acinar dysplasia, benign prostatic hyperplasia, BPH, atypical
adenomatous hyperplasia (AAH), adenosis, prostate-specific antigen, PSA, digital
rectal examination, DRE, proliferative inflammatory atrophy, lobular atrophy,
postatrophic hyperplasia, atypical basal cell hyperplasia, cribriform
hyperplasia, radiation-induced metaplasia, prostatitis

Contributor Information and Disclosures

Author

Stanley A Brosman, MD, Clinical Professor,
Department of Urology, University of California at Los Angeles Medical
School
Stanley A Brosman, MD is a member of the following medical societies:
Alpha Omega Alpha, American Academy of Pediatrics, American Association for
Cancer Research, American Association for the Advancement of Science, American
College of Surgeons, American Medical Association, American Society of Clinical
Oncology, American Urological Association, Association of Clinical Research
Professionals, International Society of Urological Pathology, Société
Internationale d'Urologie (International Society of Urology), Society for Basic
Urologic Research, Society of Surgical Oncology, Society of Urologic Oncology,
and Western Section American Urological Association
Disclosure: Nothing to
disclose.

Medical Editor

Erik T Goluboff, MD, Professor, Department of
Urology, College of Physicians and Surgeons, Columbia University; Director of
Urology, Allen Pavilion, New York Presbyterian Hospital
Erik T Goluboff, MD
is a member of the following medical societies: Alpha Omega Alpha, American
Medical Association, American Urological Association, Medical Society of the
State of New York, New York Academy of Medicine, Phi Beta Kappa, and Society for
Basic Urologic Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior
Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Dan Theodorescu, MD, PhD, Paul Mellon
Professor of Urologic Oncology, Department of Urology, University of Virginia
Health Sciences Center
Dan Theodorescu, MD, PhD is a member of the following
medical societies: American Cancer Society, American College of Surgeons,
American Urological Association, Medical Society of Virginia, Society for Basic
Urologic Research, and Society of Urologic Oncology
Disclosure: Nothing to
disclose.

CME Editor

J Stuart Wolf Jr, MD, FACS, David A Bloom
Professor of Urology, Director of Division of Minimally Invasive Urology,
Department of Urology, University of Michigan
J Stuart Wolf Jr, MD, FACS is a
member of the following medical societies: American College of Surgeons,
American Urological Association, Catholic Medical Association, Endourological
Society, Society for Urology and Engineering, Society of Laparoendoscopic
Surgeons, Society of University Urologists, and Society of Urologic Oncology

Disclosure: Terumo Corporation Consulting
fee Consulting; Omeros Corporation Consulting
fee Consulting

Chief Editor

Edward David Kim, MD, FACS, Professor of
Surgery, Division of Urology, University of Tennessee Graduate School of
Medicine; Consulting Staff, University of Tennessee Medical Center
Edward
David Kim, MD, FACS is a member of the following medical societies: American
College of Surgeons, American Society for Reproductive Medicine, American
Society of Andrology, American Urological Association, and Tennessee Medical
Association
Disclosure: Lilly Consulting
fee Consulting; Astellas Consulting fee Speaking and
teaching; Indevus Consulting fee Speaking and teaching

Further Reading

For more information, see Medscape’s Prostate Cancer Resource Center.

© 1994-

by Medscape.
All Rights
Reserved
(http://www.medscape.com/public/copyright)