The Pathology of Prostate Cancer: From Population Studies to the Molecule
Moderators: Dr. John R. Srigley and Dr. Rodolfo Montironi
Section 4 -
High-Grade Prostatic Intraepithelial
David G. Bostwick, M.D., M.B.A., F.C.A.P.
Medical Director, Bostwick Laboratories
Richmond , Virginia
High-grade prostatic intraepithelial neoplasia (PIN ) is the earliest accepted stage in
carcinogenesis, possessing most of the phenotypic, biochemical, and genetic changes of cancer without
invasion into the fibromuscular stroma.
PIN is defined as an abnormal epithelial proliferation
within pre-existing ducts and ductules, with nucleomegaly and nucleolomegaly involving at least 10% of
The term "PIN " is usually used today as a synonym for high grade PIN (formerly
PIN 2 and 3 on a 1-3 scale). The high level of interobserver variability and apparent lack of predictive
value with low grade PIN limits its clinical utility,  and most pathologists do not routinely report
this finding except in research studies. Thus, PIN is now used interchangeably with high-grade PIN by
most investigators. Interobserver agreement for high grade PIN is "good to excellent".
such as dysplasia, malignant transformation, carcinoma in situ, and intraductal carcinoma are
Epidemiology of PIN
In the United States, an estimated 1,300,000 prostate biopsies are performed annually and in 2006,
27,350 Americans will die of prostate cancer, and 234,460 new cases will be diagnosed.  The mean
incidence of isolated high-grade PIN is 9% (range 4–16%) of prostate biopsies, similar to our personal
experience in Richmond, Virginia in 2005, representing 115,000 annual new cases of high-grade PIN without
cancer diagnosed (Table 1, 2)
The incidence and extent of PIN increase with patient age (Table 1)
An autopsy study of
step-sectioned whole mount prostates from older men showed that the prevalence of PIN in prostates with
cancer increased with age, predating the onset of carcinoma by more than five years.  A similar study
of young men revealed that PIN is first seen in men in their twenties and thirties (9% and 22% frequency,
respectively}, and preceded the onset of carcinoma by more than ten years.
Most foci of PIN in
young men were low grade, with increasing frequency of high grade PIN with advancing age. The
volume of high grade PIN also increased with patient age. 
Table 1: Prevalence of High-Grade PIN in the United States
| ||High-grade ||US population* ||Number of|
|Age ||% PIN ||(Thousands) ||PIN|
|40-49 ||15.2 || 20,550 ||3,123,600|
|50-59 ||24.0 || 14,187 ||3,404,880|
|60-69 ||47.3 || 9,312 ||4,404,576|
|70-79 ||58.4 || 6,926 ||4,044,784|
|80-89 ||70.0 || 2,664 ||1,864,800|
| ||Total || 53,639,000 ||16,842,640|
Table 2. Incidence Of Isolated High-Grade Pin In Prostatic Needle Biopsies
|Reference ||Patient Population ||No. men ||Incidence of PIN (%)|
|Mettlin et al., 1991  ||American Cancer Society National Prostate Cancer Detection Project ||327 ||5.2|
|Feneley et al., 1997  ||Screening population in Gwent, England, 1991-1993 ||212 ||19.8|
|Hoedemaeker et al., 1999  ||PSA screening study in Rotterdam , Netherlands ||1824 ||0.7|
|Postma et al., 2004 ||Screening population in Rotterdam , Netherlands (1st round} ||4,117 ||0.8|
|Postma et al., 2004  ||Screening population in Rotterdam , Netherlands (2nd round, performed at a 4-year interval from the 1st round} ||1,840 ||2.5|
|Lee et al., 1989  ||Consecutive biopsies of hypoechoic lesions at St. Joseph Mercy Hospital ||256 ||11|
|Bostwick et al., 1995  ||Consecutive biopsies at Mayo Clinic ||200 ||16.5|
|Bostwick et al., 1995  ||Consecutive biopsies at Glendale Hospital (CA.} ||200 ||10.5|
|Langer et al., 1996  ||Consecutive biopsies at University of Pennsylvania Med. Ctr. ||1275 ||4.4|
|Wills et al., 1997  ||Consecutive biopsies at Johns Hopkins Hospital ||439 ||2.7|
|Feneley et al., 1997  ||Consecutive biopsies at University College London Hospitals, 1988-1994 ||1,205 ||10.9|
|Feneley et al., 1997  ||Consecutive biopsies of symptomatic men at St. Bartholomew's Hospital, London, 1993-1994 ||118 ||24.6|
|Skjorten et al., 1997 ||Consecutive biopsies from 1974-1975 at Ullevaal and Lovisenberg Hospitals, Oslo, Norway ||79 ||7.6|
|Perachino et al., 1997  ||Consecutive biopsies ||148 ||14.1|
|O'dowd et al., 2000  ||Consecutive biopsies at UroCor Inc., Oklahoma City, 1994-1998. ||132,426 ||3.7|
|Borboroglu et al., 2001  ||Consecutive biopsies ||1,391 ||5.5|
|Lefkowitz et al., 2001  ||Consecutive biopsies at the Manhattan Veterans Administration Medical Center ||619 ||16.6|
|San Francisco et al., 2003  ||Consecutive biopsies 1996-1997 ||387 ||12.6|
|Roscigno et al., 2004 ||Consecutive biopsies at San Raffaele Hospital, Milan, Italy. ||2,314 ||3.9|
|Abdel-Khalek et al., 2004  ||Consecutive biopsies at Urology and Nephrology Ctr, Mansoura University, Mansoura, Egypt, 1997-2002 ||3,081 ||2.7|
|Alsikafi et al., 2001  ||Consecutive biopsies at Section of Urology, University of Chicago, 1998-1999 ||485 ||4.3|
|Gupta et al., 2004  ||Consecutive biopsies at St. John Hospital and Medical Ctr, Detroit, 2001-2002 ||933 ||12.3|
|Gupta et al., 2004  ||Consecutive biopsies at St. John Hospital and Medical Ctr, Detroit, 1998-2000 ||515 ||13.5|
|Kobayashi et al., 2004  ||Consecutive biopsies at Hamamatsu Rosai Hospital, Hamamatsu, Japan ||104 ||20.2|
|Naya et al., 2004  ||Consecutive biopsies at University of Texas M. D. Anderson Cancer Ctr, Houston, 1997-2003 ||1,086 ||8.7|
|Moore et al., 2005  ||Consecutive biopsies at Albany Medical College and Stratton Veterans Administration Med. Ctr 1998-2003 ||1,188 ||2.5|
|Tunc et al., 2005  ||Consecutive biopsies at University of Istanbul, Turkey ||505 ||12.8|
|Girasole et al., 2006  ||Consecutive biopsies at OUR LabTM 1998 to 2004 ||40,966 ||3|
Race and geographic location also appear to influence the incidence of high-grade PIN.  When
specific age groups were compared between races, there were notable differences in the frequency of
high-grade PIN. For example, African-American men had a greater prevalence of high-grade PIN than
Caucasians in the 50–60 year-old age group, the decade preceding the manifestation of most clinically
detected prostate cancers.
African-American men also had the highest incidence of prostate
cancer (about 50% more than Caucasians).
In contrast, Japanese men living in
Osaka, Japan, had a significantly lower incidence of high-grade PIN compared to men residing in the
United States, and Asians have the lowest clinically detected rate of prostate cancer.
Interestingly, Japanese men diagnosed with high-grade PIN also had an increased likelihood of developing
prostate cancer, indicating that high-grade PIN is also a precursor of clinical prostate cancer in Asian
men. ,  The differences in the frequency of high-grade PIN in the 50–60 age group across races
essentially mirror the rates of clinical prostate cancer observed in the 60–70-year-old age group. ,
The likely causal association of high-grade PIN with prostatic adenocarcinoma is supported by the
observation that the prevalence of both high-grade PIN and cancer increase with patient age and that
high-grade PIN precedes the onset of prostate cancer by less than one decade (Table 1).
The severity and frequency of high-grade PIN in prostates with cancer are greatly increased
(73% of 731 specimens) when compared to prostates without cancer (32% of 876 specimens).
When high-grade PIN is found on sextant needle biopsy, there is a 50% risk of finding carcinoma on
subsequent biopsies within 3 years,  although this risk is lower when more than six cores are
obtained; this decline in predictive value is expected given the increased sampling for cancer with a
greater number of core biopsies.
Incidence of PIN
The incidence of PIN varies according to the population of men under study (Table 2).
lowest likelihood is in men participating in PSA screening and early detection studies, with an incidence
of PIN in biopsies ranging from 0.7 to 20%.
Men seen by urologists in practice have PIN in 4.4– 25% of contemporary needle biopsies. Those
undergoing transurethral resection have the highest likelihood of PIN, varying from 2.8 to 33% (Table 3).
In such cases, all tissue should be examined, but serial sections of suspicious foci
are usually not necessary. Unfortunately, needle biopsy specimens fail to show the suspicious focus on
deeper levels in about half of cases, often precluding assessment by immunohistochemistry and compounding
the diagnostic dilemma.
Table 3. Incidence Of Isolated High Grade Pin In Prostatic Turps
|Reference ||Specimen ||Patient Population ||Number of men ||Incidence of PIN (%)|
|Gaudin et al., 1997  ||TURP ||Consecutive TURPs without cancer at Johns Hopkins Hospital ||158 ||3.2|
|Pacelli and Bostwick, 1997  ||TURP ||Consecutive TURPs without cancer at Mayo Clinic ||570 ||2.8|
|Skjorten et al., 1997  ||TURP ||Consecutive TURPs from 1974-1975 at Ullevaal and Lovisenberg Hospitals, Oslo, Norway ||731 ||33|
Diagnostic Criteria of PIN
There are four main patterns of high grade PIN : tufting, micropapillary, cribiform, and
flat. (Figures 1-4).
 The tufting pattern is the most common, present in
97% of cases, although most cases have multiple patterns. There are no known clinically important
differences between the architectural patterns, and their recognition appears to be only of diagnostic
utility. Sporadic retorspective reports have suggested that the cribriform or micropapillary patterns
may indicate higher risk of coexistent cancer, but this has been repeatedly refuted. Other unusual
patterns of PIN include the signet ring-cell pattern, small cell neuroendocrine (oat-cell) pattern,
mucinous pattern, microvacuolated (foamy-gland) pattern, and inverted (hobnail) pattern (Figures 5-8).
 The presence of extensive PIN appears to be more predictive of
cancer than the more common isolated single acinus with PIN .
There is inversion of the normal orientation of epithelial proliferation with PIN; proliferation in
the benign epithelium normally occurs in the basal cell compartment, whereas, in PIN , the greatest
proliferation occurs on the luminal surface, similar to pre-invasive lesions in the colon (tubular
adenoma) and other sites.
PIN spreads through prostatic ducts in multiple different patterns, similar to prostatic carcinoma.
In the first pattern, neoplastic cells replace the normal luminal secretory epithelium, with preservation
of the basal cell layer and basement membrane. This pattern often has a cribriform or near-solid
appearance. Foci of high grade PIN are usually indistinguishable from intra-ductal/intra-acinar spread
of carcinoma by routine light microscopy.  In the second pattern, there is direct invasion through
the ductal or acinar wall, with disruption of the basement
membrane and basal cell layer. In the third pattern, neoplastic cells invaginate between the basal
cell layer and columnar secretory cell layer ("pagetoid spread"), a very rare finding.
Early stromal invasion, the earliest evidence of carcinoma, occurs at sites of acinar outpouching and
basal cell disruption in acini with high grade PIN. Such microinvasion is present in about 2% of high
power microscopic fields of PIN, and is seen with equal frequency in all architectural patterns. 
The mean volume of PIN in prostates with cancer is 1.2–1.32 cc, and the volume increases with
increasing pathologic stage, Gleason grade, positive surgical margins, and perineural invasion.
These findings underscore the close spatial and biologic relationship of PIN and cancer, and may result
from an increase in PIN with increasing cancer volume.
PIN and cancer are usually multicentric.
PIN is multicentric in 72% of radical
prostatectomies with cancer, including 63% of those involving the non-transition zone and 7% of those
involving the transition zone; 2% of cases have concomitant single foci in all zones.  The peripheral
zone of the prostate, the area in which the majority of prostatic carcinomas occur (70% or more), is also
the most common location for PIN.
Cancer and PIN are
frequently multicentric in the peripheral zone, indicating a "field" effect similar to the
multicentricity of urothelial carcinoma of the bladder.
High-grade PIN and prostate cancer are morphometrically and phenotypically similar. High-grade PIN
occurs primarily in the peripheral zone and is seen in areas that are in continuity with prostate cancer.
High-grade PIN and prostate cancer are multifocal and heterogeneous.
Increasing rates of aneuploidy and angiogenesis as the grade of PIN progresses are
further evidence that high-grade PIN is precancerous
Prostate cancer and
high-grade PIN also have similar proliferative and apoptotic indices.
It is often difficult with small foci in needle biopsies to separate cancer from suspicious foci
(atypical small acinar proliferation suspicious for but not diagnostic of malignancy (ASAP)) when there
is coexistent high-grade PIN; the difficulty is based on the inability to separate tangential cutting of
the larger pre-existing acini of PIN (that may appear as small separate adjacent acini) from the smaller
discrete acini of cancer. In such cases, we prefer the term PIN + ASAP (referring to the coexistence of
the two lesions--high-grade PIN and ASAP-- in the same high-power microscopic field) to avoid
over-diagnosis of tangential cutting of PIN and cancer.
Recent renewed efforts to introduce the term "intraductal carcinoma" rely on the abandoned concept
that dysplasia (defined here as malignancy arising at that specific site within the epithelium) can be
separated reliably from intraductal/intra-acinar spread of cancer (defined here as extension of malignant
cells through the pre-existing lumens of the prostate); however, this concept was rejected by consensus
on multiple occasions owing to lack of reproducible criteria for making this distinction, and the
non-committal term intraepithelial neoplasia was internationally adopted and repeatedly reconfirmed as it
begs the question of site of origin of the process. Those who persist with the belief that "intraductal
carcinoma" can be diagnosed rely on proximity of the epithelial abnormality to invasive cancer, but this
criterion is arbitrary and not based on valid objective confirmatory data. More importantly, there is no
clinical utility at present that requires separation of dysplasia and intraductal/intra-acinar spread of
cancer—the clinical response is the same. It is conceivable that future studies may allow diagnostic
separation of dysplasia and intraductal/ intra-acinar spread of cancer; if so, then these steps in the
biologic progression of prostate cancer may be shown to have differential predictive value for prostate
cancer. We agree that identification of subsets of high-grade PIN that indicate greater risk of cancer
is a clinically important area of investigation, but such attempts to date have been fruitless.
Useful Immunohistochemical Markers for the diagnosis of PIN
Select antibodies such as anti-keratin 34βE12 (high molecular weight keratin) or p63 may be used
to stain tissue sections for the presence of basal cells,  recognizing that PIN retains an intact or
fragmented basal cell layer whereas cancer does not.
Monoclonal basal cell-specific antikeratin 34βE12 stains virtually all the normal basal cells of
the prostate, with continuous intact circumferential staining in many instances. There is no staining in
the secretory and stromal cells. This marker is the most commonly used immunostain for prostatic basal
and methods of use with paraffin-embedded sections have been
optimized.  Keratin
34βE12 is formalin sensitive and requires pretreatment by enzymes or heat if formalin-based
fixatives are used. After pepsin predigestion or microwaving, there is progressive loss of
immunoreactivity from one week or longer of formalin fixation. Heat-induced epitope retrieval with a hot
plate yielded consistent results with no decrease in immunoreactivity with as long as 1 month of formalin
fixation.  The staining intensity was consistently stronger at all periods of formalin fixation when
the hot plate method was used, compared with pepsin predigestion or microwaving. Weak immunoreactivity
was rarely observed in cancer cells after hot plate treatment, but not with pepsin predigestion or
microwave antigen retrieval. Steam-EDTA in combination with protease significantly enhanced basal cell
immunoreactivity compared with protease treatment alone in benign prostatic epithelium.  Nonreactive
benign acini were always the most peripheral acini in a lobule, a small cluster of outpouched acini
furthest from a large duct, or the terminal end of a large duct.  More proximal acini had a
discontinuous pattern of immunoreactivity. Electron microscopy showed occasional acini with luminal
cells abutting the basement membrane, without the interposition of basal cell cytoplasm, and other acini
with extremely attenuated basal cell cytoplasmic processes containing sparse bundles of intermediate
Increasing grades of PIN are associated with progressive disruption of the basal cell layer, according
to studies utilizing anti-keratin 34βE12. Basal cell layer disruption is present in 56% of cases of
high grade PIN, and is more frequent in acini adjacent to invasive carcinoma than in distant acini. The
amount of disruption increases with increasing grades of PIN. Early invasive carcinoma occurs at sites
of glandular outpouching and basal cell discontinuity in association with PIN.  The cribriform pattern
of PIN may be mistaken for the cribriform pattern of adenocarcinoma, and the use of anti-keratin
staining is often useful in making this distinction.  Cancer cells consistently fail to react with
this antibody, although admixed benign acini may be misinterpreted as cancerous staining. Thus,
immunohistochemical stains for antikeratin 34βE12 may show the presence or absence of basal cells in
a small focus of atypical glands, helping to establish a benign or malignant diagnosis respectively. We
believe that this antibody can be employed successfully if one judiciously interprets the results in
combination with the light microscopic findings; relying solely on the absence of immunoreactivity
(absence of basal cell staining) to render the diagnosis of cancer is without precedent in diagnostic
immunohistochemistry and is discouraged.  Nonetheless, some studies have noted that the rate of
equivocal cases can be reduced considerably, 
by 68%, 
or from 5.1 to 1.0%  by addition of this
immunohistochemical marker. Evaluation of prostate biopsies following therapy such as radiation therapy
may be one of the most useful roles for antikeratin 34βE12 (see below).
In addition to PIN and cancer, basal cell layer disruption or loss also occurs in inflamed acini,
atypical adenomatous hyperplasia, and postatrophic hyperplasia, and may be misinterpreted as cancer if
one relies exclusively on the immunohistochemical profile of a suspicious focus. Furthermore, basal
cells of Cowper's glands may not express keratin 34βE12, 
although this has been disputed. 
Rare (0.2%) cases of adenocarcinoma have been reported that express keratin 34βE12, including foci
of metastatic high-grade adenocarcinoma; these cases did not appear phenotypically to be basal
cell/adenoid cystic carcinoma. 
Basal cell hyperplasia is a histologic mimic of cancer, and use of anti-keratin 34βE12 is
recommended in any equivocal cases that include this lesion in the differential considerations as it is
invariably positive in that lesion.
CK5 and CK14 mRNA and protein are expressed in the basal cells of benign acini and PIN, and CK14 mRNA
is present in low levels in the luminal cells of the most of some foci of PIN; thus, if PIN is derived
from basal cells, as is currently believed, CK14 translation is depressed and a low level of CK14 mRNA
may persist.  CK8 mRNA and protein were constitutively expressed in all epithelia of normal and
abnormal prostate tissues. CK19 mRNA and protein were expressed in both basal and luminal cells of
benign acini. CK16 mRNA was expressed in a similar pattern as CK19, but CK16 protein was not
We routinely generate unstained intervening sections of all prostate biopsies for possible future
immunohistochemical staining, recognizing that small foci of concern are often lost when the tissue block
is recut; one study reported loss of the suspicious focus in 31 of 52 cases. 
Other markers of basal cells include proliferation markers, differentiation markers, and genetic
markers. The preferential localization of many of these markers in basal cells but not in secretory
cells suggests that they play a role in growth regulation. P63 is a recently introduced nuclear marker
that may be useful for separating PIN and cancer from benign mimics. Basal cells display
immunoreactivity at least focally for keratins 5, 10, 11, 13, 14, 16, and 19; of these, only keratin 19
is also found in secretory cells.
Keratins found exclusively in the secretory cells
include 7, 8, and 18. Basal cells usually do not display immunoreactivity for prostate-specific antigen
(PSA), prostatic acid phosphatase (PAP), and S-100 protein, and only rare single cells stain with
chromogranin and neuron-specific enolase. Conversely, the normal secretory luminal cells invariably
stain with PSA and PAP. Prostatic basal cells do not usually display myoepithelial differentiation, ,
 in contrast with basal cells in the breast, salivary glands, pancreas, and other sites.
A new molecular marker, racemase (alpha-methylacyl-CoA racemase, P504S) was introduced for separating
benign and neoplastic acini. This marker has proven useful for evaluation of ASAP (atypical small acinar
proliferation suspicious for but diagnostic of cancer) and separation of cancer from hormonally-treated
benign acini. Its advantage over anti-keratin 34βE12 is its positive granular cytoplasmic staining
in cancer cells, with little or no staining in benign acini. In PIN, monoclonal and polyclonal
antibodies to alpha-methylacyl-CoA racemase, P504S were positive in 77% and 91%, respectively, 
consistent with previously published studies.
Since racemase is not specific for prostate cancer
and is present in high grade PIN (> 90%), this staining must be interpreted with caution and the
diagnosis of PIN or prostate cancer should be rendered only with convincing histologic evidence.  The
gene for alpha-methylacyl-CoA racemase (AMACR) is greatly overexpressed in prostate cancer cells.
Racemase is a well-characterized enzyme that catalyzes the conversion of several
(2R)-methyl-branched-chain fatty acyl-CoAs to their (S)-stereoisomers. Analysis of mRNA levels of
racemase revealed an average upregulation of nine-fold in prostate cancer. Other reports have
substantiated the differential expression of this enzyme protein in benign and cancerous prostate tissues
Genetic and Molecular Changes
High-grade PIN and prostate cancer share similar genetic alterations.
For example, the
frequent 8p12–21 allelic loss commonly found in prostate cancer was also found in microdissected PIN.
 Other examples of genetic changes found in carcinoma that already exist in PIN include loss of
heterozygosity (LOH) at 8p22, 12pter-p12,
and gain of chromosomes 7, 8, 10, and
Loss of heterozygosity frequencies at 13q (one of the most common chromosomal alterations in
high-stage prostate cancer) is 0% vs. 49% in PIN and clinical prostate cancer,
Alterations in oncogene bcl2 expression and RER+ phenotype are similar for PIN and prostate cancer.
In summary, these clinical and molecular studies taken together provide strong evidence that
high-grade PIN alerts both the clinician and the patient that progression to clinically significant
prostate cancer is likely.
PIN is associated with progressive abnormalities of phenotype and genotype, which are intermediate
between normal prostatic epithelium and cancer, indicating impairment of cell differentiation and
regulatory control with advancing stages of prostatic carcinogenesis.  There is
progressive loss of some markers of secretory differentiation, including prostate-specific antigen,
prostatic acid phosphatase, secretory proteins, 
cytoskeletal proteins,  glycoproteins such as
blood group antigens, neuroendocrine cells, p-cadherin, 
fibroblast growth factor-2, 
prostate-specific transglutaminase, 
androgen receptor expression,  insulin-like
growth factor binding protein-3,
and telomerase.  A member of the CIP/KIP family of
cyclin-dependent kinase inhibitory proteins, p27KIP1, also showed significant reduction in expression in
PIN, cancer, and metastatic cancer when compared with benign prostatic epithelium.
markers show progressive increase, including human glandular kallikrein 2 (hK2),
(Her-2/neu} and c-erbB-3 oncoproteins,
mutator (RER (+))
epidermal growth factor and epidermal growth factor receptor,  type
IV Collagenase, Lewis Y antigen, TGF-alpha, apoptotic bodies,
PCNA expression, Ki-67 expression, MIB-1 expression,
aneuploidy and genetic abnormalities,
microvessel density,  Ep-Cam transmembrane
insulin-like growth factor binding protein IGFBP-rP1, and p53 mutations,  although
one group found no p53 expression immunohistochemically in PIN.  Prostatic-specific membrane antigen,
an abundant transmembrane glycoprotein, shows increased expression in PIN and cancer when compared with
and this expression was unaffected by short-term androgen deprivation
therapy. A progressive loss of expression of annexin I, a calcium- and phospholipids-binding protein, in
PIN and with the increasing histological grade of prostate cancer may serve as a useful marker of
prostate cancer development and progression. 
Over-expression of Aurora-A (Aurora 2 kinase, STK-15),
a protein found in centrosomes, is present in some normal and the majority of high-grade PIN. 
Estrogen receptor alpha is present in up to 28% of cases of PIN and 43% of cancers, but estrogen receptor
beta is absent; 
prolactin receptor expression is increased in PIN.  Promoter methylation of
GSTP1 gene is mainly observed in prostate carcinoma and in about 70% of high-grade PIN lesions and may
represent an important marker for the transition of in situ to invasive neoplasia. 
A model of prostatic carcinogenesis has been proposed based on the morphologic continuum of PIN and
the multistep theory of carcinogenesis. 
Microvessel Density Is Increased In PIN
PIN is virtually always accompanied by a proliferation of small capillaries in the stroma, despite
separation from the underlying vasculature by a basal cell layer and basement membrane. It is likely
that PIN initially coopts adjacent vessels, similar to other tumors, and that these vessels soon regress,
only to be followed by vigorous angiogenesis at the cancer's edge. A critical balance exists between the
proangiogenic vascular endothelial growth factor and the angiogenic antagonist angiopoietin-2.
Angiogenin is a polypeptide involved in the formation and establishment of new blood vessels necessary
for growth and metastasis of numerous malignant neoplasms, including prostatic cancer. In a recent
study, the investigators reported a percentage of cells staining positively for angiogenin in benign
prostatic glandular epithelium, high-grade prostatic intraepithelial neoplasia, and prostatic cancer, in
17%, 58%, and 60%, respectively, confirming the potential role that angiogenin plays in neoplastic
Microvessel density is higher in high-grade PIN than in adjacent benign prostatic tissue, and the
capillaries are shorter, more widely spaced, have more open lumina and curvaceous external contours, and
are lined by a greater number of endothelial cells. The degree of microvessel density in PIN is
intermediate between benign epithelium and cancer, lending support to the concept of PIN as the precursor
of prostate cancer. Microvessel density is significantly higher in cases with PIN associated with
prostate cancer than those with isolated PIN or benign prostatic hyperplasia alone.  Inhibition of
angiogenesis may be an effective method of chemoprevention, for men at high risk such as those who have
high grade PIN. It should be well tolerated in most adults because angiogenesis under typical conditions
is needed only for reproduction and wound healing. 
Animal Models of PIN and Prostate Cancer
Several different animal models of prostate cancer have demonstrated that high-grade PIN is in the
direct causal pathway to prostate cancer. 
The transgenic mouse model of prostate cancer (TRAMP) has
been shown to mimic human prostate cancer.
The transgenic mouse model of prostate cancer
(TRAMP) has been shown to mimic human prostate cancer. In the TRAMP model, the Probasin promoter-SV40
large T antigen (PB-Tag) transgene is expressed specifically in the epithelial cells of the murine
prostate under the control of the probasin promoter. The probasin promoter is androgen-dependent. As a
result, this model has several advantages over currently existing models: 1) Mice develop progressive
forms of prostatic epithelial hyperplasia and high-grade PIN as early as 10 weeks and invasive prostate
adenocarcinoma around 18 weeks of age; 
2) The pattern of metastatic spread of prostate cancer mimics
that of human prostate cancer with common sites of metastases being lymph node, lung, kidney, adrenal
gland and bone; 3) The development as well as the progression of prostate cancer can be followed within a
relatively short period of 10–30 weeks; 4) Spontaneous prostate tumors arise with 100% frequency; and 5)
Animals may be screened for the presence of the prostate cancer transgene prior to the onset of clinical
prostate cancer. Another animal model id the transgenic mouse model that contains a probasin promoter
that controls the ECO:R1 gene. This gene product has been implicated in the induction of genomic
instability.  Prostates from these animals were followed prospectively from 4 to 24 months of age and
showed the progressive presence of mild to severe hyperplasia, low-grade PIN, high-grade PIN, and then
well-differentiated adenocarcinoma of the prostate.  Some investigators demonstrated that
transgenic mice that have prostatic overexpression of AR protein develop focal areas of high-grade
The mechanism of prostate carcinogenesis appears to involve estrogenic signaling. Wang et al. 
treated wild-type mice with testosterone propionate and estradiol for 4 months. These mice developed
prostatic hyperplasia, high-grade PIN, and invasive prostate cancer. When α-ERKO mice, mice that
have the ERα genetically knocked out, are treated the same way, they develop prostatic hyperplasia,
but not high-grade PIN or invasive prostate cancer.  Similarly, a prospective, placebo-controlled
study of TRAMP mice treated with an antiestrogen, Acapodene (toremifene) was performed to
pharmacologically antagonize ERα. These acapodene-treated TRAMP mice had a reduction in high-grade
PIN, significant decrease in prostate cancer incidence, and an increase in animal survival. Thus,
estrogenic signally through ERα may play a key role;  prostate carcinogenesis and that high-grade
PIN was observed to be in the direct causal pathway to prostate cancer.
The dog is the only nonhuman species in which spontaneous prostate cancer occurs, and, like humans,
the rate of canine prostate cancer increases with aging.
High-grade PIN has been also observed
in the prostates of these animals.
Canine high-grade PIN shows cytological features identical
to the human counterpart, including cell crowding, loss of polarity, and nuclear and nucleolar
enlargement. Like prostatic adenocarcinoma, high-grade PIN also increases with aging.  High-grade
PIN appears to represent an early event in prostate carcinogenesis that occurs with high frequency within
the prostates of pet dogs sharing the same environment as humans. In this model, high-grade PIN was
determined to be an intermediate step between benign epithelium and invasive carcinoma. Thus, like the
transgenic mouse models, the canine model supports high-grade PIN as part of a continuum in the
progression of prostate cancer.
Clinical Significance of PIN
PIN Does Not Elevate PSA
Biopsy remains the definitive method for detecting PIN and early invasive cancer. Serum PSA
concentration may be elevated in patients with PIN, 
although these results have been refuted. ,
 There is a poor correlation of PIN and PSA density according to studies of radical prostatectomy
specimens and preoperative serum.  Mean PSA increased from 8.4 to 11.6 ng/mL in patients with PIN who
developed cancer within two years; those with PIN who did not develop cancer during this interval had an
increase in PSA from 4.8 to 5.9 ng/mL or decrease from 5.1 to 4.6 ng/mL; however, these
findings have not been confirmed.
The ratio of free to total PSA is the same for patients with high-grade PIN and cancer, unlike low
grade PIN and hyperplasia, although this has also been refuted. Many patients in these studies were
later found to have cancer, so the elevation in serum PSA concentration and its derivatives may have
resulted from the undetected cancer.
Transrectal Ultrasound Cannot Detect PIN
By transrectal ultrasound, PIN may be hypoechoic like carcinoma, although these findings have not been
Today, most urologists and radiologists do not believe that PIN is detectable by
transrectal ultrasound because PIN is a microscopic finding which is below the detection threshold for
this form of imaging.
Men with PIN Develop Prostate Cancer
As a risk factor, the presence of isolated PIN in a set of sextant needle biopsies connotes a risk
ratio of 14.9. PIN is a far stronger predictor for subsequent cancer than the independent predictors of
patient age (>65 years old vs. ≤ 65 years old) and serum prostate specific antigen (PSA) (>4
ng/ml vs. ≤ 4 ng/ml); for these, the respective risk ratios are 3.5 and 3.64.  PIN coexists
with cancer in more than 85% of cases, according to studies employing whole-mounted totally embedded
prostates. In one report, the likelihood of finding cancer increased with the biopsy time interval. The
investigators reported a 32% incidence of cancer if repeat biopsy was performed within 1 year, compared
with a 38% incidence in biopsies obtained after 1 year.  Other series have also found a high
predictive value of PIN for cancer, although recent reports based on obtaining a greater number of cores
shows a lower predictive value (Table 4).
These data underscore the strong
association of PIN and adenocarcinoma and indicate that vigorous diagnostic follow up is needed.
Multiple factors account for the decline in the predictive accuracy of high-grade PIN for cancer. The main factor is use of extended biopsy techniques that result in more thorough
prostate sampling and in higher cancer detection rates; thus, there is a smaller pool of patients with an
isolated diagnose of PIN. Another factor is the lower detection rate for, and difficulty in the
detection of, the remaining small cancers; larger significant tumors may also escape detection. These
factors lead to a higher frequency of negative repeat biopsies. These results may reflect a new steady
state and a newly reached low plateau in the predictive accuracy of these markers. In a recent report,
the investigators demonstrated that with 6 core biopsies for both the initial and re-biopsy the risk of
cancer was 14.1% compared to 31.9% in the group that had 8 core or more biopsy on followup with an
initial 6 core biopsy. They found that the risk of cancer on biopsy within 1 year following a diagnosis
of PIN (13.3%) is relatively low if good sampling (8 or more cores)
is initially performed. 
Table 4. Cancer Detection In Patients With High Grade
|Publication Date ||Study Dates ||Cores ||Reference ||No. of Subjects With Repeat Biopsy (ies) ||PIN cases With PCa at Follow-Up (%)|
|1995 ||1987-1993 ||1-8 ||Davidson  ||100 ||35|
|1996 ||1990-1994 ||NS ||Raviv  ||48 ||48|
|1996 ||1991-1993 ||F ||Langer  ||53 ||27|
|1996 ||Not stated ||4 ||Shepherd  ||66 ||47|
|2000 ||1995-1998 ||Mixed ||Kamoi  ||45 ||22|
|2000 ||1994-1998 ||Mixed ||O'dowd  ||1,306 ||23|
|2001 ||1991-1998 ||NS ||Kronz  ||245 ||32|
|2001 ||1998-1999 ||NS ||Alsikafi  ||21 ||14|
|2001 ||Not stated ||6 ||Maatman  ||86 ||16|
|2001 ||1995-2000 ||6 ||Borboroglu  ||45 ||44|
|2001 ||1999-2001 ||12 ||Lefkowitz ||43 ||2|
|2002 ||1995-2002 ||10-12 ||Roscigno  ||47 ||45|
|2003 ||1996-1997 ||EXT ||San Francisco  ||47 ||24|
|2003 ||2001-2003 ||6 ||Goeman  ||63 ||27|
|2004 ||1997-2003 ||EXT ||Naya  ||47 ||11|
|2004 ||1999-2002 ||4-15 ||Bishara  ||132 ||29|
|2004 ||Not stated ||20 ||Rabets  ||38 ||18|
|2004 ||1997-2002 ||11 ||Abdel-Khalek  ||83 ||36|
|2004 ||2000-2003 ||6 ||Postma  ||101 ||13|
|2005 ||1998-2003 ||EXT ||Moore  ||22 ||5|
|2005 ||2000-2002 ||6-18 ||Schlesinger  ||204 ||23|
|2005 ||1996-2000 ||6 ||Gokden  ||190 ||30|
|2005 ||1998-2003 ||6 or EXT ||El-Fakharany  ||585 ||25|
|2005 ||2001-2003 ||NS ||Leite  ||142 ||13|
|2006 ||1997-2001 ||Mixed ||Herawi  ||332 ||21|
|2006 ||1997-2001 ||Mixed ||Herawi  ||323 ||13|
|2006 ||1998-2004 ||2-4 ||Girasole CR ||358 ||22|
|2006 ||1999-2004 ||6 ||Hussein  ||17 ||41|
|2006 ||1999-2005 ||12 ||Keith  ||48 ||31|
EXT, extended in all cases (>8); F, fewer than sextant; NS, not specified; PCa, prostate cancer.
Another plausible explanation regarding those results may be related to the fact that backward
probability is usually based on retrospective evidence, whereas forward probability is usually based on
prospective evidence; consequently, backward probability is often easier to determine. Many researchers
do not distinguish between these two probabilities, falsely concluding that the probability of a risk
factor in patients with the disease is the probability of the disease occurring in people with the risk
factor. The use of backward probability as a substitute for forward probability is a common fallacy in
medical practice and may result in false attribution of causation. 
High-grade PIN in transurethral resection specimens is also an important predictive factor for
Among 14 patients with PIN and BPH followed for up to 7 years (mean,
5.9 years), three (21.4%)
developed prostatic cancer.  Mean serum PSA concentration was higher than
in those who did not develop cancer (8.1 vs 4.6 ng/ml, respectively). All subsequent cancers apparently
arose in the peripheral zone and were detected by needle biopsy. Thus, all tissue should be submitted by
the pathologist for examination when high-grade PIN is found in TURP specimens. The high predictive
value of PIN for the development of subsequent cancer warrants reporting the presence of PIN in TURP
specimens, according to the Cancer Committee of the College of American Pathologists. Conversely, a
study showed that PIN in the transition zone and central zone from Norwegian men is not predictive of
subsequent cancer development. 
As the significance of PIN in initial biopsies as a marker of prostate cancer in repeat biopsies has
been extensively investigated (see Table 4), little is known of the actual rate of cancer in the whole
prostate in this setting because repeat biopsies may miss the area of cancer. Some investigators aimed
to define a more precise positive predictive value of isolated PIN in initial biopsies in predicting
cancer in the prostate gland and found that clinically significant prostate cancer were associated with 4
out of 11 biopsies positive for PIN as compared with 3 out of 21 biopsies negative for PIN. The positive
predictive value of PIN was 64%, with a sensitivity of 28% and a specificity of 81%. 
Androgen Deprivation Therapy Eliminates PIN
There is a marked decrease in the prevalence and extent of high-grade PIN in cases after androgen
deprivation therapy when compared with untreated cases.
This decrease is accompanied by
epithelial hyperplasia, cytoplasmic clearing, and prominent glandular atrophy, with decreased ratio of
glands to stroma. These findings indicate that the dysplastic prostatic epithelium is hormone dependent.
In the normal prostatic epithelium, luminal secretory cells are more sensitive to the absence of androgen
than basal cells, and these results indicate that the cells of high-grade PIN share this androgen
sensitivity. The loss of some normal, hyperplastic, and dysplastic epithelial cells with androgen
deprivation is probably due to acceleration of programmed single cell death. A report suggested that PIN
is not substantially decreased after hormonal therapy, but those authors failed to use current criteria
for PIN, so the results are not comparable. 
Neoadjuvant hormone deprivation with monthly leuprolide and flutamide 250mg p.o. t.i.d. for three
months resulted in a 50% reduction in high-grade PIN. Longer therapy with 6 months of neoadjuvant
androgen deprivation therapy prior to radical prostatectomy in the European Randomized Study of Screening
for Prostate Cancer (ERSPC)
study reduced high-grade PIN even more.  Flutamide decreased
the prevalence and extent of high-grade PIN and induced epithelial atrophy.  There is also evidence
that cessation of flutamide resulted in return of high-grade PIN.
The results of 5-alpha-reductase (finasteride) treatment in high-grade PIN are controversial and the
cumulative number of cases studied is probably too small to draw firm conclusions.  Two reports found
no apparent effect on the histologic appearance or extent of high-grade PIN,
whereas a third
study of three cases described atrophy and involution with decreased prevalence. 
Radiation Therapy Eliminates PIN
The prevalence and extent of PIN is decreased after radiation therapy.
However, one study
paradoxically noted a higher incidence (70%)
of PIN after radiation therapy than expected,  but they
failed to employ accepted diagnostic criteria for PIN, so their results are not comparable with others.
A report from Memorial Sloan-Kettering found PIN in 8.8% of biopsies following a course of 3-dimensional
external beam conformal radiation therapy. 
Following radiation therapy, PIN retains the features characteristic of untreated PIN, and is readily
recognized in tissue specimens. The key pathologic features include nuclear crowding, nuclear
overlapping and stratification, nuclear hyperchromasia, and prominent nucleoli. The basal cell layer is
present, but often fragmented; racemase shows strong apical to diffuse cytoplasmic staining. The most
common patterns of PIN are tufting and micropapillary, similar to those reported in untreated PIN.
The long-term efficacy of radiation treatment may depend on eradication of cancer as well as
pre-cancerous lesions that may otherwise lead to evolution of secondary metachronous invasive cancers.
Identification of residual or recurrent cancer portends a worse prognosis. The questions remain whether
recurrent cancer after irradiation is due to regrowth of incompletely eradicated tumor or progression
from incompletely eradicated PIN. Further studies of salvage prostatectomy specimens and post-RT needle
biopsies are justified in an attempt to establish the significance of high-grade PIN as a source of
long-term treatment failure among these patients. If PIN is associated with treatment failure, adjuvant
chemoprevention strategies that ablate this lesion may reduce the risk of late cancer recurrence.
Should Men with High Grade PIN Be Treated?
The clinical importance of recognizing PIN is based on its strong association with prostatic
carcinoma. PIN has a high predictive value as a marker for adenocarcinoma, so its identification in
biopsy specimens warrants further search for concurrent invasive carcinoma. If all procedures fail to
identify coexistent carcinoma, close surveillance and follow-up are indicated. As high-grade PIN
progresses, the likelihood of basal cell layer disruption increases, very much like what is observed for
carcinoma in situ (CIS) of the urinary bladder. CIS of the urinary bladder, like PIN, may become
invasive and is treated aggressively. The standard of care for management of CIS of the bladder is
intravesical instillation of chemotherapy or BCG, and, in some cases, radical cystectomy.
Follow-up biopsy is suggested for patients with PIN at three to six month intervals for two years, and
thereafter at twelve-month intervals for life.
Some urologists perform "saturation" biopsies,
consisting of more than 12–15 biopsies in one session, often with brief general anesthesia in the
operating theatre, in an effort to definitively exclude cancer. Most authors agree that the
identification of PIN in the prostate should not influence or dictate therapeutic decisions.  We are
aware of 21 radical prostatectomies that were purposely (3 cases) or inadvertently performed (18 cases)
in patients whose biopsies contained only high grade PIN; all but two of the cases contained
adenocarcinoma in the surgical specimen (DG Bostwick, personal communication, 2003).
Currently, routine treatment is not available for patients who have high-grade PIN. Prophylactic
radical prostatectomy or radiation is not an acceptable treatment for patients who have high-grade PIN
only.  The development and identification of acceptable agents to treat high-grade PIN would fill a
therapeutic void. As noted above, androgen deprivation therapy and radiation therapy induce
acinar atrophy and apoptosis that result in regression of high-grade PIN.
Chronic therapy, however, would most likely be required to prevent new high-grade PIN lesions from
invading and becoming clinical prostate cancer. Although more toxicity is likely to be tolerated for the
treatment agents targeted to regress or inhibit high-grade PIN, as compared to treating
healthy patients to reduce prostate cancer incidence, androgen deprivation therapy has too many adverse
effects in men to be clinically useful. New agents with better safety and lower side effect profile are
greatly needed since patients may be taking the agent at least until they attain 70 years of age. 
Toremifene (AcapodeneTM) is a selective estrogen receptor modulator that eliminates high-grade
PIN and reduces the incidence of prostate cancer. After 4 months of toremifene (60 mg/day orally for 4
months), 72% of men treated (vs. 17.9% of controls) had no high-grade PIN on subsequent prostate
biopsies.  In another study, cumulative risk of prostate cancer was reduced in patients taking
toremifene 20 mg compared with placebo (24.4% vs. 31.2%) with an annualized rate of prevention of 6.8
cancers per 100 men treated.  Among patients with no biopsy evidence of cancer at baseline and 6
months, the 12-month incidence of prostate cancer was reduced by 48.2% with toremifene 20 mg compared
with placebo (9.1% vs. 17.4%). The 20-mg dose was most effective, but the cumulative and 12-month
incidences of prostate cancer were lower with each toremifene dose versus placebo (cumulative risk:
29.2% for 40 mg, 28.1% for 60 mg; 12-month incidence 14.3% for 40 mg, 13.0% for 60 mg).
Green tea catechins (GTCs) also may reduce the incidence of prostate cancer. Catechins are
antioxidants in the class of polyphenols called flavonols. After 6 months of green tea catechins (600
mg/day orally), 3.3% of the men with PIN had cancer compared with 30% of those who took placebo.
Selenium and Vitamin E are also under investigation as putative chemopreventive agents.
PIN offers promise as an intermediate endpoint in studies of chemoprevention of prostatic carcinoma.
Recognizing the slow growth rate of prostate cancer and the considerable amount of time needed in animal
and human studies for adequate follow-up, the non-invasive precursor lesion PIN is a suitable
intermediate histologic marker to indicate subsequent likelihood of cancer.
PIN Does Not Predict Cancer Recurrence
PIN was not predictive of PSA (biochemical) failure at 32 months in patients undergoing radical
prostatectomy and androgen deprivation therapy. 
Differential Diagnosis of PIN
The histologic differential diagnosis of PIN includes lobular atrophy, post-atrophic hyperplasia,
atypical basal cell hyperplasia (Figure 9), cribriform hyperplasia (Figure 10), and metaplastic changes associated with radiation (Figure 11), infarction, and prostatitis (Table 5). Many of these display
architectural and cytologic atypia, including enlarged nucleoli, and small specimens, and cauterized or
distorted specimen. Cribriform adenocarcinoma, ductal (endometrioid) carcinoma, and urothelial carcinoma
involving prostatic ducts and acini may also be confused with PIN (Figure 12).
Biopsies submitted with incomplete patient history should be interpreted with caution. In one study, the
authors reported that the proliferative activity, defined as Ki-67 labeling index, was higher in ductal
carcinoma than in PIN (33% vs. 6%).(209) Stratified epithelium in non-cribriform glands of prostate
cancer can also resemble high grade PIN. Recognition of this fact and immunohistochemical evaluation of
stratified glands may be indicated to correctly diagnose those glands as prostate cancer. 
PIN may be overdiagnosed as adenocarcinoma. Our retrospective review of transurethral resections from
the Mayo Clinic files between 1960 and 1970 revealed that PIN was often diagnosed as adenocarcinoma. 
Similarly, fine needle aspiration of the prostate may yield cell clusters of PIN that are overdiagnosed
as cancer; this issue is critically important to consider in evaluating studies from Sweden and other
countries that have, perhaps erroneously, relied on fine needle aspiration diagnoses for patients treated
with watchful waiting (expectant management).
Mimics of high-grade PIN (overdiagnosis of PIN) in 60 consecutive cases
(Bostwick DG, Ma J. In press, 2006)
|Mimic of PIN ||Number of Cases (%)|
|Basal cell hyperplasia ||12 (20%)|
|Benign proliferative epithelium (non-central zone) ||10 (17%)|
|Low-grade PIN ||10 (17%)|
|Reactive changes ||10 (17%)|
|Atypical basal cell hyperplasia ||7 (12%)|
|Central zone epithelium ||5 (8%)|
|Urothelium ||2 (3%)|
|Seminal vesicle ||1 (2%)|
|Cribriform hyperplasia ||1 (2%)|
|Post-atrophic hyperplasia ||1 (2%)|
|Atrophy ||1 (2%)|
High grade PIN is the most likely precursor of prostatic adenocarcinoma, according to virtually all
available evidence. PIN is associated with progressive abnormalities of phenotype and genotype, which
are intermediate between normal prostatic epithelium and cancer, indicating impairment of cell
differentiation and regulatory control with advancing stages of prostatic carcinogenesis. There is
progressive loss of some markers of secretory differentiation, whereas other markers show progressive
The clinical importance of recognizing PIN is based on its strong association with prostatic
carcinoma. PIN has a high predictive value as a marker for adenocarcinoma, and its identification in
biopsy specimens of the prostate warrants further search for concurrent invasive carcinoma. Studies to
date have not determined whether PIN remains stable, regresses, or progresses, although the implication
is that it can progress.
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