Prostate Cancer: Diagnosis 2004
David G. Bostwick
- Describe the diagnostic criteria and clinical significance of PIN and ASAP
- Explain the strengths and limitations of Gleason grading in contemporary needle biopsies.
- Understand the factors that the pathologist relies upon in predicting cancer aggressiveness in biopsy specimens.
- Address the value of extent of prostate cancer in needle biopsies and the potential limitations.
Identification of PIN, ASAP, or both in a needle biopsy warrants repeat biopsy for
concurrent or subsequent cancer. Prostate cancer has been identified in about 50% of subsequent biopsies
for PIN and up to 60% for ASAP, but most early reports were based on quadrant or sextant biopsies.
Recent studies with octant or more biopsies have shown that the predictive accuracy for cancer is lower
for PIN and ASAP, particularly in highly screened patient populations when compared with previously
reported unscreened populations; however, both PIN and ASAP are still significant predictors of cancer
compared with historic controls.
There are two principle findings in contemporary needle biopsies of the prostate that provide the
greatest predictive value for cancer progression: grade and extent of cancer in the specimen. Both
findings should be reported, according to recent recommendations by the College of American Pathologists
and the World Health Organization. Problems with grading include interobserver and intraobserver
variability and imprecise predictive value. In biopsies, these problems are compounded by small sample
size, tumor heterogeneity, and undergrading of biopsy samples. Also, significant histologic changes in
adenocarcinoma occur as a result of androgen deprivation therapy that make grading difficult and of
In prostate needle biopsies, two histologic findings-- high-grade prostatic intraepithelial neoplasia
(PIN) and atypical small acinar proliferation (ASAP)-- are each highly predictive of subsequent prostatic
adenocarcinoma, and the identification of either without concurrent cancer warrants follow-up with repeat
PIN is present in 4-16% of contemporary needle biopsies, whereas ASAP is
observed in a bout 2% of biopsies.
PIN and ASAP can occur together in
the same biopsy set without concomitant cancer. We refer to the coexistence of the two lesions in the
same high-power microscopic field as "PIN/ASAP".
HIGH-GRADE PROSTATIC INTRAEPITHELIAL NEOPLASIA (PIN)
High-grade PIN is the earliest accepted stage in carcinogenesis, possessing most of the
phenotypic, biochemical, and genetic changes of cancer without invasion of through the basement membrane
and into the fibromuscular stroma.
PIN is the defined as an abnormal epithelial
proliferation within the pre-existing ducts and ductules with nucleomegaly and nucleolomegaly involving
at least 10% of the cells .
The diagnostic term "prostatic intraepithelial neoplasia"
has been endorsed at every multidisciplinary and pathology consensus meeting on the subject around the
world since into introduction in 1986
,and the interobserver agreement
between pathologists has been determined to be "good to excellent"
for high-grade PIN.
Terms such as dysplasia, malignant transformation, carcinoma in situ, and intraductal carcinoma are
Prostatic intraepithelial neoplasia was originally graded from 1–3, but current recommendations
recognize two grades of PIN (low grade and high grade). Grade 1 is synonymous with low-grade prostatic
intraepithelial neoplasia (low grade PIN), whereas grades 2 and 3 are considered together as high-grade
PIN; currently, conventional use of the term "PIN" without qualification refers to only high-grade PIN.
High-grade PIN is a standard diagnosis that must be included as part of the reported pathologic
evaluation of prostate biopsies, transurethrally resected prostate chips, and radical prostatectomy
The high level of interobserver variability and apparent lack of
predictive value for cancer with low grade PIN limits its clinical utility, and most pathologists do not
report this finding except in research studies, including us.
Epidemiology of PIN
In the United States, an estimated 1,300,000 prostate biopsies are performed annually to
detect about 230,900new cases of prostate cancer.
The incidence of isolated high-grade
PIN averages 9% (range 4–16%) of prostate biopsies, representing 115,000 new cases of high-grade PIN
without cancer diagnosed each year (Table 1). 
Table 1: Estimated frequency of men harboring high-grade PIN in the United States
|Age || High-grade % PIN ||US population|
(1990 U.S. census)
|Number of PIN|
|40-49||15.2 || 20,550,000|| 3,123,600|
|50-59||24.0 || 14,187,000|| 3,404,880|
|60-69||47.3 || 9,312,000 ||4,404,576|
|70-79||58.4 || 6,926,000 ||4,044,784|
|80-89||70.0 || 2,664,000 ||1,864,800|
| || Total || 53,639,000 || 16,842,640|
The incidence and extent of PIN appear to 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 precedes the onset of carcinoma by more than ten years.
} The volume of
high grade PIN also increases with patient age. 
Race and geographical location may also influence the incidence of high-grade PIN.
 When age groups are compared between races, there are significant differences in the
frequency of high-grade PIN. For example, African-American men have a greater prevalence of high-grade
PIN than Caucasians in the 50–60 year age group, the decade preceding the manifestation of most
clinically detected prostate cancers.
African-American men also have the highest
incidence of prostate cancer (about 50% more than Caucasians).
contrast, Japanese men living in Osaka, Japan have 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
Interestingly, Japanese men diagnosed with high-grade PIN also have an
increased likelihood of developing prostate cancer, indicating that high-grade PIN is also a precursor of
clinical prostate cancer in Asian men.  Thus, the differences in the frequency of
high-grade PIN in the 50–60 year age group across races essentially mirror the rates of clinical prostate
cancer observed in the 60–70 year age group.
The causal association of high-grade PIN with prostatic adenocarcinoma is based on the
fact that the prevalence of both high-grade PIN and prostate cancer increases 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 is 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 over 3 years  , although this risk is cut in half when twice as many
cores are obtained. There is also evidence to suggest that high-grade PIN may represent a precursor to a
more aggressive form of prostate cancer phenotype than to those that are more likely to remain indolent.
Incidence of PIN
The incidence of PIN varies according to the population of men under study (Table 2).
The lowest likelihood is in men participating in PSA screening and early detection
studies, with an incidence of PIN in biopsies ranging from 0.7– 20%.
Men seen by
urologists in practice have PIN in 4.4– 25% of needle biopsies. Those undergoing transurethral resection
also have a high likelihood of PIN, varying from 2.8 – 33%.
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, precluding assessment by immunohistochemistry and compounding the diagnostic dilemma.
Diagnostic Criteria of PIN
There are four main patterns of high grade PIN: tufting, micropapillary, cribiform, and
flat.  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 of high grade PIN, and their recognition appears to be only of diagnostic utility. Nonetheless,
one report suggested that the cribriform pattern may indicate higher risk of coexistent cancer, but this
has been refuted. Other unusual patterns of PIN include the signet ring-cell pattern, small cell
neuroendocrine pattern, and foamy-gland pattern.  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.
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 ||330 ||5.2|
|Richie et al., 1994  ||Screening population ||163 ||8.6|
|Feneley et al., 1997  ||Screening population in Gwent, England, 1991-1993 ||212 ||20|
|Hoedemaeker et al., 1999  ||PSA screening study in Rotterdam (Netherlands) ||1824 ||0.7|
|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 ||5.5|
|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|
|Feneley et al., 1997  ||Consecutive biopsies at University College London Hospitals 1988-1994 ||1205 ||11|
|Feneley et al., 1997  ||Consecutive biopsies of symptomatic men at St. Bartholomew's Hospital, London, 1993-1994 ||118 ||25|
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 intraductal/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 with all architectural
patterns.  In equivocal cases, we prefer the term PIN/ASAP to avoid over-diagnosis of
tangential cutting of PIN as cancer.
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.
} 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
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
High-grade PIN and prostate cancer are multifocal and
Increasing rates of aneuploidy and angiogenesis as the grade of PIN
progresses are further evidence that high-grade PIN is a precancer.
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) 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.
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/intracinar 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.
Useful Immunohistochemical Markers for the diagnosis of PIN (Table 3)
The secretory luminal cells of high-grade PIN invariably stain with PSA and PAP. Select antibodies
such as anti-keratin 34ß-E12 (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. Increasing grades of PIN are associated with
progressive disruption of the basal cell layer, according to studies utilizing anti-keratin 34ß-E12.
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 out-pouching and basal cell
discontinuity in association with PIN.  The cribriform pattern of PIN may be mistaken for
cribriform adenocarcinoma or ductal carcinoma, and the use of anti-keratin staining
Table 3. Markers of Basal Cell Differentiation in the Prostate
|Biomarker ||Function ||Findings|
|PCNA ||Cell proliferation marker ||Up to 79% of labeled cells are basal cells|
|MIB 1 ||Cell proliferation marker ||Up to 77% of labeled cells are basal cells|
|Ki-67 ||Cell proliferation marker ||Up to 81% of labeled cells are basal cells|
|Androgen Receptors ||Nuclear receptors which are necessary for prostatic epithelial growth ||Strong immunoreactivity; also present in cancer cells|
|Prostate-specific antigen ||Enzyme which liquifies the seminal coagulum ||Present in rare basal cells; mainly in secretory luminal cells|
|Keratin 8.12 ||Keratins 13, 16 ||Strong immunoreactivity|
|Keratin 4.62 ||Keratin 19 ||Moderate immunoreactivity|
|Keratin PKK1 ||Keratins 7,8,17,18 ||Moderate immunoreactivity|
|Keratin 312C8-1 ||Keratin 14 ||Strong immunoreactivity|
|Keratin 34B-E12 ||Keratins 5,10,11 ||Strong immunoreactivity; most commonly used for diagnostic purposes|
|P63 ||A member of the p53 family. ||Stains basal cells nuclei; most commonly used for diagnostic purposes|
|Epidermal Growth Factor Receptor ||Membrane bound 170-kd glycoprotein which mediates the activity of EGF ||Strong immunoreactivity; rare in cancer|
|CuZn-Superoxide Dismutase ||Enzyme which catalyzes superoxide anion radicals ||Strong immunoreactivity|
|Type IV Collagenase ||Enzyme involved in extracellular matrix degradation ||Strong immunoreactivity; decreased in cancer|
|Type VII Collagen ||Part of the hemidesmosomal complex ||Strong immunoreactivity; lost in cancer|
|Integrins alpha1,2,4,6,and v; Beta 1 and 4 ||Extracellular matrix adhesion molecules ||Strong immunoreactivity; decrease in most with cancer, although alpha 6 and Beta 1 are retained|
|Estrogen Receptors ||Hormone receptor ||Moderate immunoreactivity|
|bcl-2 ||Oncoprotein which suppresses apoptosis ||Strong immunoreactivity; also found in most cancers|
|c-erbB2 ||Oncogene protein in the EGF family ||Strong immunoreactivity; also found in most cancer|
|Glutathione S- transferase gene (GSTP1) ||Enzyme which inactivates electrophilic carcinogens ||Strong immunoreactivity; rare in cancer|
|C-CAM ||Epithelial cell adhesion molecule || Strong immunoreactivity; absent in cancer|
|TGF-B ||Growth factor which regulates cell proliferation and differentiation ||Strong immunoreactivity; absent in cancer|
|Cathepsin B ||Enzyme which degrades basement membranes; may be involved in tumor invasion and metastases ||Present in many basal cells, and rarely in luminal secretory cells; also found in cancer cells|
|Progesterone Receptors ||Hormone receptor ||Moderate immunoreactivity|
is invaluable in making this distinction.  There are a number of other markers of basal
cell markers, including nuclear stain for p63 that is gaining in popularity in recent years.
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 PIN and ASAP (atypical
small acinar proliferation suspicious for but diagnostic of cancer) and separation of cancer from
hormonally-treated benign acini. It's advantage over anti-keratin 34ß-E12 is positive granular
cytoplasmic staining in cancer cells, with little or no staining in benign acini. The gene for
alpha-methylacyl-CoA racemase (AMACR) is greatly overexpressed in prostate cancer cells.
Differential Diagnosis of PIN
The histologic differential diagnosis of PIN includes lobular atrophy, post-atrophic
hyperplasia, atypical basal cell hyperplasia, cribriform hyperplasia, and metaplastic changes associated
with radiation, infarction, and prostatitis. 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. Biopsies submitted with incomplete patient history should be
interpreted with caution.
PIN may be overdiagnosed as adenocarcinoma. Our retrospective review of transurethral
resections from the Mayo Clinic files between 1960–1970 revealed that PIN was often diagnosed as
adenocarcinoma.  Similarly, fine needle aspiration of the prostate may yield cell clusters
of PIN that are over-diagnosed 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).
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
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.
The PSA antigen is excreted to the outside via the prostatic ducts. PIN does not
significantly elevate serum PSA concentration is due to the architectural integrity of the gland lumina
involved by PIN. Conversely, the cells of the neoplastic acinar structures found in prostate cancer
release prostate specific antigen into the surrounding stroma where it is absorbed into the bloodstream,
raising serum PSA.
Transrectal Ultrasound Cannot Detect PIN
By transrectal ultrasound, PIN may be hypoechoic like carcinoma, although these findings have not been
confirmed.  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
ratioof 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% incidenceof 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).
Results in recent cohorts of patients with isolated PIN biopsied between 1999 and 2001
listed in Table 1B. The reported frequencies of cancer at follow-up were 23%, 25%, 27%, and 28%.
High grade PIN in transurethral resection specimens is also an important predictive
factor for prostate cancer (Table 5).
These data underscore the strong association of PIN and adenocarcinoma and indicate
that vigorous diagnostic follow up is needed.
Table 4. Cancer Detection in Patients with High Grade Pin
|Reference ||Pt. population ||No. men ||% patients with cancer|
on repeat biopsy
|Brawer et al.  ||Urology practice ||10 ||100|
|Ellis and Brawer  ||Urology practice ||5 ||100|
|Aboseif et al.  ||Urology practice ||24 ||79.1|
|Weinstein and Epstein  ||Urology practice ||19 ||53|
|Keetch et al.  ||PSA screening ||37 ||51|
|Davidson et al.  ||Two urology practices ||100 ||35|
|Markham  ||Urology practice ||32 ||41|
|Raviv et al.
||Urology practice ||48 ||47.9|
|Langer et al.  ||Urology practice ||53 ||27|
|Berner et al.  ||Oncology practice ||37 ||38|
|Shepherd et al.  ||PSA screening ||66 ||58|
|Perachino et al.  ||Urology practice ||21 ||71.1|
|Krishnamurthi et al.  ||Urology practice ||74 ||31|
|Rovner et al.  ||Urology practice ||19 ||31.6|
|Park et al.  ||Urology practice ||43 ||51|
|Kronz et al.  ||Urology practice ||245 ||32|
|Igel et al.  ||Urology practice ||88 ||43|
|Park et al.  ||Urology practice ||104 ||22|
|Gokden et al.  ||Urology practice ||221 ||28%|
|Sakr et al  ||Urology Practice ||540 ||27%|
|Siever et al.  ||Urology Practice ||145 ||25%|
|Schlesinger & Bostwick  ||Urology Practice ||335 ||23%|
|Bishara et al.  ||Urology Practice ||132 ||28.8%|
|Mendrinos et al.  ||Urology Practice ||80 ||67% for PIN in multiple cores|
38.6% for isolated PIN
|Pierson et al.  ||Urology Practice ||249 ||21%|
|Varma et al.  ||Urology Practice ||37 ||5.4%|
We believe that the following factors account for the decline in the predictive accuracy
of HGPIN for cancer.The major role is played by use of extended biopsy techniques that result in more
thorough prostate sampling and in higher cancer detection rates. Conversely, by these actions there
remains a smaller pool of patients who receive isolated diagnoses of PIN. Another contributor is the
lower detection rate for, and difficulty in the detection of, the remaining small cancers; larger
Table 5. Incidence of Isolated High Grade Pin in Prostatic Transurethral Resections
|Reference ||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|
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.
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 recent 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 PO TID 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
Radiation Therapy Eliminates PIN
The prevalence and extent of PIN is decreased after radiation therapy.
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 recent report from Memorial Sloan-Kettering found PIN in 8.8% of biopsies
following a course of 3-dimensional external beamconformal 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. 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 at three to six month intervals for two years, and thereafter at
twelve-month intervals for life.
Some urologists have performed "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. Newer 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
 . Acapodene, an anti-estrogen is currently in a Phase IIb multicenter, randomized,
prospective placebo-controlled human clinical trial to determine if it can treat high-grade PIN and
reduce prostate cancer incidence; preliminary results are encouraging. 
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. 
ATYPICAL SMALL ACINAR PROLIFERATION
SUSPICIOUS FOR BUT NOT DIAGNOSTIC OF MALIGNANCY (ASAP)
ASAP Is a Valid Diagnostic Category
The diagnostic quandary in cases in which the diagnosis of ASAP is rendered usually results
from one or a combination of the reasons listed in Table 6. All of these may hinder a definitive
Table 6. Reasons for ASAP Diagnosis
- Small number of acini in the focus of concern
- Small focus size, average 0.4 mm in diameter 
- Lesion breakage at core tip, indicating that the focus is incompletely sampled
- Lack of clear histologic detail (e.g., thick section, overstained nuclei, etc.)
- Distortion of acini
- Lack of convincing malignant features, e.g, small number of cells with nucleomegaly or nucleolomegaly
- Clustered growth pattern mimicking a benign process such as atypical adenomatous hyperplasia or atrophy
- Loss of the focus of concern in deeper levels obtained for high molecular weight cytokeratin or racemase immunostains.
- Focally positive high molecular weight cytokeratin or negative racemase immunostain in focus.
- Presence of associated high-grade PIN raising the possibility of tangential cutting of PIN.
- Prominent inflammation in which the adjacent benign acini show distortion, raising concern for overdiagnosis of reactive changes or atrophy.
- Inflammatory cellular reactive atypia with nuclear and nucleolar enlargement
diagnosis of carcinoma, but, in such cases, the possibility cannot be definitively excluded. The need
for this category is based on our "absolute uncertainty" regarding the diagnosis. That this need exists
is manifested by the variety of terms or synonyms currently in use that include the word "atypical" to
describe this diagnosis, although ASAP is now the preferred term that is most widely used. The diagnosis
of ASAP indicates to the clinician that the biopsy in question exhibits histologic features that are
neither clearly malignant nor clearly benign and that follow-up of the patient is warranted.
For pathologists, two questions need to be answered prior to the diagnosis of ASAP or cancer in a
small lesion: "Would you be absolutely confident of this biopsy diagnosis if it were followed by a
negative radical prostatectomy?"; and similarly "Can you confidently support a diagnosis of malignancy
based solely on this biopsy?" If the answer to either question is "No," then we recommend use of the
more conservative diagnosis of ASAP. In this setting, we believe that "ASAP" is a valid diagnostic
category as long as it is employed judiciously and that maximum information has been obtained from the
available tissue (see Methods). Other evidence useful in supporting a cancer diagnosis, including
patient age, serum PSA concentration, and high-molecular weight cytokeratin and racemase expression
cannot substitute for convincing hematoxylin and eosin (H&E) microscopic findings. To avoid bias,
the above information should be considered only after microscopic examination is performed.
ASAP Predicts Cancer
In studies published between 1997 and 2001, the reported
incidence of prostate cancer in repeat biopsies following a diagnosis of ASAP ranged from 34% to 60%.
These studies involved patient cohorts that underwent biopsy between 1989 and
1996, with the exception of one investigator who reported a cohort in which biopsies were performed
between 1995 and 2000  .
In a recent study, the investigators reported the results of follow-up prostate needle
biopsies in a patient population with long term close clinical follow-up, in whom earlier, smaller
lesions are detected. Only patients biopsied after January 1, 2000 were included in order to accurately
reflect the current state of clinical practice. The follow-up cancer detection rates were compared to
rates in earlier cohorts of patients, in whom longitudinal repetitive PSA screening had been more
recently introduced. They found that the contemporary predictive value of ASAP for subsequent cancer was
This is compared with historic rates of 34-60% for ASAP listed in Table 6.
 These findings indicate that the predictive accuracies of ASAP for cancer have decreased
since the original studies on this topic were published. A similar lower cancer detection rate of 34%
for ASAP was also noted in a 1998 report. 
Table 7. Cancer Detection in Patients with Asap
|Date of publication ||Study dates ||Authors ||# Subjects with repeat biopsy(ies) ||Frequency of diagnosis ||ASAP?CA|
|1997 ||1993-1995 ||Cheville et al.  ||n=25 ||ASAP- 4.8% ||60%|
|1997 ||1993-1996 ||Iczkowski et al.  ||n= 33 || ||45%|
|1998 ||1991-1995 ||Iczkowski et al.  ||n= 295 || ||42%|
|1998 ||1989-1996 ||Renshaw et al.  ||n= 59 || ||34%|
|1999 ||1992-1993 ||Chan et al.  ||n= 144 || ||49%|
|2001 ||1991-1998 ||Park et al.  ||n= 45 || ||51%|
|2001 ||1995-2000 ||Borboroglu et al.  ||n= 48 ||ASAP- 3.8%|| 48%|
|2002 ||1990-2002 ||Iczkowski et al.  ||n= 129 ||ASAP- 3.2% ||45%|
|2003 ||2001-2003 || Schlesinger & Bostwick  ||n= 78 || ||37%|
|2004 ||?-2004 ||Fadare et al.  ||n=55 ||ASAP-2.8% ||37.5%|
During the past two decades, there has been a significant downward stage migration and decrease in
positive surgical margins. The following factors may account for the decline in predictive
accuracies of PIN and ASAP for prostate cancer. A major contribution is the use of extended biopsy
techniques that increase the diagnostic yield for cancer. Chen et al. demonstrated via a computer
generated composite image the frequent origin of tumors from the lateral base and medial apex, sites not
sampled by sextant  . Cancer detection rates of 16- 35% or higher in extended vs. sextant
biopsies have been shown by other investigators.
Extended biopsy is now recognized as
a common method of prostate sampling
. Conversely, more thorough prostate sampling
reduces the number of undetected cancers, particularly significant cancers, leaving a smaller pool of
patients to receive isolated diagnoses of PIN, ASAP, or PIN/ASAP. Smaller tumor volumes in the remaining
cancers make detection more difficult, and thus higher likelihood of a negative repeat biopsy.
Following the introduction of PSA screening
, an unprecedented and
continuous increase in localized and regional prostate cancers continued through 1992 and then decreased.
 Beginning in 1992, there were also declines in distant stage disease and in 2-year
cancer mortality rates [SEER data].  These observations probably reflect lead time bias,
as well as what one author referred to as a "harvesting" effect, with reference to advanced tumors.
 In 2003, the relatively dramatic decreases in prostate cancer volumes and stage have
already occurred. Thus, any subsequent evolution in cancer characteristics will, of necessity, be of
lesser magnitude. We believe that our findings reflect some of these less dramatic changes, and that a
steady state may have been reached.
Clinical Significance of ASAP
Like high-grade prostatic intraepithelial neoplasia, ASAP holds a significant
predictive value for cancer on repeat biopsy. When repeat biopsy is undertaken, use of at
least sextant (or more) sampling method is best. Sampling only the side or sextant site initially
diagnosed as ASAP missed cancer in 39% of patients whose cancer was detected exclusively at other sites.
 The repeat biopsy rates by urologists in 1997 reports were 46%  and 47%
 but, in more recent studies, ranged up to 60%,  similar to our 56% rate.
In one report, the investigators found that ASAP represented undersampled cancer in at
least 40% of cases. They observed that some men with ASAP in first set of biopsy and benign or
high-grade prostatic intraepithelial neoplasia findings on the second biopsy may still have had cancer
that was not detected.  False-negative results on repeat sextant biopsy in untreated men
with documented adenocarcinoma occurred in 23% of repeat sextant biopsies.  These results
also suggest that the current practice of performing 6 to 12 biopsies per prostate is not lowering the
frequency of ASAP diagnosis. A declining volume of residual cancer at prostatectomy was noted 5 years
ago,  and is probably reflective of increased screening and multiple sampling. Thus, as
smaller volume cancers are detected through increased sampling, many will be undersampled and not
resolvable by immunostains, leading to an irreducible rate of ASAP diagnosis.
The combination of high grade prostatic intraepithelial neoplasia and atypical small
acinar proliferation lesions, found in up to 16% of all biopsies, has an intermediate predictive value of
33% for cancer.  Thus, it is slightly lower than isolated ASAP but higher than isolated
PIN. In previous reports, associated PIN occured in 23%  and 31% of ASAP cases
 , respectively. In a recent study, the frequency of associated PIN was higher, occurring
in 41% of total cases containing "ASAP" in the diagnosis,, but most foci were not adjacent or
In a similar investigation, a lesion containing both PIN and ASAP was reported to have a
46% follow-up cancer detection rate. This lesion was strictly defined, and corresponded to our
definition of contiguous PIN/ASAP lesions.  Three reasons might account for the difference
in predictive values, 33% vs. 46%, seen in these 2 studies. First, the latter study was restricted to
contiguous cases; this type of lesion might have an intrinsically higher predictive value for cancer than
in our series, in which the frequency of contiguous lesions was about half. The selection bias present
in cases referred for consultation also may have influenced the study results as compared with unselected
primary cases in another study cohort. Also, the number of patients reported in each study was few
enough that skewing of data in either direction might occur. In another small study of 12 patients with
PIN and adjacent atypical glands (ASAP), 75% had cancer on repeat biopsy.  Additional
studies involving larger numbers of patients with a combination of PIN and ASAP lesions would be of
High grade PIN is the most likely precursor of prostatic adenocarcinoma, according to
virtually all available evidence. 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.
The predictive accuracy for cancer is lower for both PIN and
for ASAP in a highly screened patient population compared with previously reported populations. However,
the presence of either or both histologic markers in a biopsy set is still a significant predictor for
concurrent/subsequent Cancer compared to the cohorts of patients lacking these lesions. Thus, even
though the predictive value of these lesions has decreased, they remain as significant risk factors for
|Histologic grade is a powerful predictive factor in prostatic adenocarcinoma, and is valuable even in contemporary 18-gauge needle biopsies. More than 40 grading systems have been proposed since the pioneering work of Broders more than 70 years ago (Broders, 1926). All systems successfully identify well differentiated adenocarcinoma which progresses slowly and poorly differentiated adenocarcinoma which progresses rapidly (Bostwick, 1994b). However, grading systems are less successful in subdividing the majority of moderately differentiated adenocarcinomas which have intermediate clinical behavior (Gleason 1966; Mostofi, 1975; Böcking et al., 1982; Gleason, 1990; Gleason, 1992).|
|Problems with grading include interobserver and intraobserver variability, imprecise predictive value, and lack of a single universal system. In biopsies, these problems are compounded by small sample size, tumor heterogeneity, and undergrading of biopsy samples. Also, significant histologic changes in adenocarcinoma occur as a result of radiation and androgen deprivation therapy which make grading difficult and of questionable value. This chapter describes the current role of grading in prostatic adenocarcinoma, correlation of biopsy grade with prostatectomy grade, and clinical significance of grade. Emphasis is placed on the Gleason grading system, the most commonly used system (Gardner et al., 1988) .|
Gleason Grading System (Veterans Administration Cooperative Urological Research Group Grading System; VACURG System)
|The Gleason grading system is based on prospective study of more than 4000 patients between 1960 and 1975, and is the de facto grading standard in the United States and other parts of the world (Gleason, 1966; Gleason, 1990; Gleason, 1992). Other systems in use internationally are the World Health Organization (Mostofi, 1975) and Böcking (Böcking et al., 1982) systems. These systems are clinically useful, showing a positive correlation with tumor volume, preoperative serum PSA concentration, the likelihood of pelvic lymph node metastases, and tumor recurrence after surgery and radiation therapy.|
|The Gleason system is based on the degree of architectural differentiation. Tumor heterogeneity is accounted for by assigning a primary pattern for the dominant grade and a secondary pattern for the non-dominant grade; the histologic score is derived by adding these two values together. Early studies described the addition of the clinical stage (1-4 scale) to create the Gleason "sum," but this did not achieve widespread use (Gleason et al., 1974). Some contemporary reports use the term sum for Gleason score (Greene et al., 1994).|
|The success of Gleason grading is due to four factors. First, histologic patterns are identified by the degree of acinar differentiation without relying on morphogenetic or histogenetic models. Second, a simplified and standardized drawing is available which has been popular among pathologists throughout the world. Third, Gleason and coworkers provided abundant prospective information that allowed objective development of this self-defining grading system which combined nine separate patterns into five grades. Finally, unlike any other grading system in the body, the Gleason system provided for tumor heterogeneity by identifying primary and secondary patterns.|
|Gleason noted that more than 50% of adenocarcinomas in his series contained two or more patterns (Gleason, 1992). Similarly, Aihara et al. recently found an average of 2.7 different Gleason grades per case (range, 1-5) in a series of 101 totally embedded prostatectomies, and more than 50% of adenocarcinomas contained at least 3 different grades (Aihara et al., 1994). The number of grades increases with increasing cancer volume, and the most common finding is high grade adenocarcinoma within a larger well or moderately differentiated adenocarcinoma (53% of cases).|
Grading needle biopsies
|Each pattern represents a blend of the growth pattern of the tumor and the amount of acinar differentiation. Recognition of these features in biopsies is frequently difficult due to small size and incomplete sampling.|
|The primary grade is the most common or predominant grade. The secondary grade is the next most common, but should comprise at least 5% of the tumor. It is often hard to apply this rule when the amount of cancer in the specimen is small; in such cases, there may be no secondary pattern, and the primary grade is simply doubled. Most cancers are moderately differentiated, so biopsies usually contain Gleason pattern 3. We report cancer as "Adenocarcinoma (Gleason #+#=#)" to avoid possible confusion of what constitutes grade and score.|
Gleason Pattern 1 (Grade 1)
|Gleason pattern 1 adenocarcinoma is uncommon and difficult to diagnose, particularly in biopsies. It consists of a circumscribed mass of simple round acini which are uniform in size, shape, and spacing. Circumscription is the single most important criterion to separate pattern 1 and pattern 2, but is usually difficult to identify in biopsies because most foci of cancer extend beyond the edge of the needle core. In such cases, it is best to consider the focus as pattern 2, recognizing that focal loss of the rounded circumscribed border disqualifies pattern 1.|
|The acini in pattern 1 are monotonously replicated, with round contours, evenly spaced acini, uniform round lumens, and distinct cell membranes. Even spacing of the acini is an important but little-appreciated criterion for pattern 1 and pattern 2 cancer. The acini are usually separated from each other by a distance of less than one acinar diameter, and may appear closely packed in some areas. Irregular spacing and separation of more than a few glands at the periphery suggests a higher grade.|
|The cells in Gleason pattern 1 tend to be rectangular, with pale or clear cytoplasm. Nuclear and nucleolar enlargement are moderate, but allow and often define separation from one of its closest mimicks, atypical adenomatous hyperplasia (AAH). In small foci on needle biopsies, this distinction may be difficult, particularly when confounding factors such as crush artifact or drying artifact is present; however, AAH is rare in needle biopsies.|
|Acidic luminal mucin is usually scant and wispy in patterns 1 and 2 carcinoma. Crystalloids are observed in more than half of cases, more than in other patterns.|
Gleason Pattern 2 (Grade 2)
|Gleason pattern 2 is very similar to pattern 1 except for the lack of circumscription of the focus, indicating the ability of the cancer to spread through the stroma. Slightly greater variation in acinar size and shape is observed, but the acinar contours are chiefly round and smoothly sculpted. Acinar packing is somewhat more variable than pattern 1, and separation is usually less than one acinar diameter. The cytologic features of pattern 2 are indistinguishable from pattern 1.|
Gleason Pattern 3 (Grade 3)
|Pattern 3 is the most common pattern of prostatic adenocarcinoma, and encompasses a wide and diverse group of lesions. This diversity is reflected in the three main variants: A,B, and C. Pattern 3A, also referred to descriptively as the large gland variant of pattern 3, is easily distinguished from pattern 3B, the small gland variant, and 3C, the cribriform variant. Mixtures of these patterns are frequently observed.|
|The hallmark of pattern 3 adenocarcinoma is prominent variation in size, shape, and spacing of acini. We often use an arbitrary cut point of greater than two-fold variation in acinar size to separate Gleason pattern 3 from pattern 2. Despite this variation, the acini remain discrete and separate, unlike the fused acini of pattern 4 (see below). Some acini of pattern 3 display apparent rigidity, with irregular sharply angulated contours and twisted elongated forms which stand in contrast with the rounded contours of lower grades. Acinar spacing is often variable, usually more than one diameter apart; however, close packing may also be prominent without acinar fusion. Acini are haphazardly arranged in the stroma, sometimes with prominent stromal fibrosis. The irregular size and spacing at the edges imparts a ragged appearance.|
|The large acinar pattern, 3A, differs from the small acinar pattern, 3B, by the average size of the acini. The cribriform pattern, 3C, is distinctive, consisting of solid aggregates of cells punctuated by fenestrations imparting a sieve-like appearance. Papillae may also be present. Ductal adenocarcinoma (endometrioid carcinoma) is included in this pattern.|
|Patterns 3B and 3C are progressively slightly more aggressive than 3A, but they often coexist and have similar cancer-specific death rates. Thus, separation of these subgrades is not necessary and could create additional problems with consistency of grading (Gleason, 1990).|
Gleason Pattern 4 (Grade 4)
|The characteristic finding of pattern 4 is fusion of acini, with ragged infiltrating cords and nests at the edges. Unlike the simple entwined acinar tubules of pattern 3, this pattern consists of an anastomosing network or spongework of epithelium.|
|The most common subtype, 4A, consists of cells with basophilic cytoplasm, unlike the clear or pale cytoplasm of 4B, the "hypernephroid" pattern. Pattern 4 adenocarcinoma is considered poorly differentiated, and is much more malignant than pattern 3.|
Gleason Pattern 5 (Grade 5)
|Pattern 5 adenocarcinoma is characterized by fused sheets and masses of haphazardly arranged acini in the stroma, often displacing or overrunning adjacent tissues. In biopsy specimens, these cases raise the serious concern for anaplastic carcinoma or sarcoma. Cases with scattered acinar lumins indicative of glandular differentiation are included within this pattern. Comedocarcinoma is an important subtype of this pattern, consisting of luminal necrosis within an otherwise cribriform pattern; only a single acinus has to contain necrosis to apply this designation. Pattern 5 also includes rare histologic variants such as signet ring-cell carcinoma and small cell undifferentiated carcinoma.|
THIRTEEN CLUES FOR GRADING NEEDLE BIOPSIES OF THE PROSTATE
(From Bostwick DG, Dundore PA. Biopsy Pathology of the Prostate. Chapman &
CLUE #1: Small foci of cancer do not necessarily mean low grade cancer.
With the advent of serum PSA and sextant biopsy, small foci of carcinoma are
frequently found in needle biopsies. However, these small foci are not low grade simply because they are
small. High grade adenocarcinoma (Gleason pattern 4 and 5) often infiltrates as irregular ribbons or
ragged masses immediately beneath the edge of the prostate, and a small portion may be sampled by biopsy,
resulting in very few malignant acini in the specimen. In rare instances, the only evidence of carcinoma
may be a few acini surrounding one or more small nerve twigs; this small focus is usually Gleason pattern
3 or 4 in our experience.
CLUE #2: It probably isn't Gleason pattern 1.
Gleason patterns 1 and 5 are the least common patterns in any prostate specimen,
including radical prostatectomies and biopsies. Pattern 1 is usually present in the transition zone, an
area infrequently sampled by needle biopsy. Further, these tumors are usually small. In a Mayo Clini
study of over 300 needle biopsies, only one had Gleason pattern 1 (secondary pattern 1; primary pattern
CLUE #3: To identify Gleason pattern 1, the cancer must be circumscribed.
The most important difference between Gleason pattern 1 and 2 is the presence or
absence of circumscription, respectively. Contemporary needle biopsy rarely provides the entire focus of
cancer for evaluation, precluding evaluation of the periphery for completeness of circumscription.
Consequently, the default grade for partially sampled low grade cancers with uniform spacing is pattern
CLUE #4: Gleason pattern 2 should satisfy the three "R's": Round, Regularly spaced, and Relatively uniform in size.
Gleason pattern 2 cancer consists of predominately round acini without sharp
angulation or distorted shape. Nearly as important as acinar roundness is spacing-- pattern 2 acini have
relatively uniform spacing throughout the focus, unlike pattern 3 with variable spacing.
CLUE #5: Gleason pattern 2 acini may be close to one another, but must have intervening stroma and no significant distortion of shape.
If significant acinar croding is present with some loss of intervening stroma between
acini, it may be more accurately considered as pattern 3. Any significant distortion of adjacent
malignant acini constitutes Gleason pattern 3.
CLUE #6: It's probably Gleason pattern 3.
The "default" grade for prostatic adenocarcinoma is pattern 3, recognizing that the
great majority of cancers fall in this pattern which encompasses the center of the normal distribution
curve. More that 80% of Gleason's original series was pattern 3. Don't be hesitant about assigning
pattern 3+3 =6 to a needle biopsy simply because the previous five cases with small foci of cancer were
the same grade.
CLUE #7: If there is a two-fold or greater variation in acinar size, it's probably Gleason pattern 3 rather than pattern 2.
When malignant acini are uniformly separated from one another, a two-fold variation in
acinar size distinguishes Gleason pattern 3 from pattern 2. Any variation in acinar size less than this
may represent Gleason pattern 2 (exceptions to this exist; see CLUE #8).
CLUE #8: Despite relative uniformity of acinar size, significant acinar angulation or distortion indicates Gleason pattern 3 rather than pattern 2.
Significant acinar angulation violates CLUE #4 above, precluding pattern 2. Some areas
of Gleason pattern 3 may have relatively uniform acinar size with or without crowding. This pattern
often has acini that are smaller than pattern 2. The lack of acinar roundness in such cases separates
pattern 3 from pattern 2.
CLUE #9: Fusion is fusion is fusion (Gleason pattern 4).
Acinar fusion separates most cases of Gleason pattern 4 and 3. This is a critical cut
point in grading prostate cancer, as pattern 4 indicates poorly differentiated cancer. Fortunately, this
is one of the most reproducible cut points due to the requirement for acinar fusion in pattern 4. If a
line can be drawn around individual acini, no mattern how tightly packed, then the acini are not fused
and it is pattern 3 (See CLUE #10).
CLUE #10: If a line can be drawn between acini that have no intervening stroma (fusion) for a length of at least 4 times the width of the acinus, this constitutes Gleason pattern 4.
Tangentially cut tubular and tortuous acini of Gleason 3 may mimick pattern 4, and
such "grade inflation" should be avoided. In difficult cases, if the length of "fusion" of the acinus of
concern is less than 4 times its width, we consider it pattern 3.
CLUE #11: If its cribriform and nearly solid, its probably Gleason pattern 4.
Cribriform acini are usually pattern 3 (with comedo necrosis, pattern 5). However,
when the sieve-like opernings lose their round rigid punched-out appearance and become collapsed and
nearly solid, it is best considered pattern 4. Similarly, when the sieve-like masses lose their round
contours, it often indicates transition to pattern 4.
CLUE #12: The loss of most acinar lumens within fused acini indicates Gleason pattern 5.
Most acinar lumens must be absent in order to separated Gleason pattern 5 from pattern
4. Tangential cutting and crush artifact may obscure or hide lumens. However, if most acini lack lumens,
it constitutes pattern 5.
CLUE #13: If in doubt, double the pattern to create the score.
With small foci of cancer, it is often best to simply double the Gleason pattern. We
invariably do this when there is less than 5% of the needle biopsy involved with cancer unless there is
an obvious secondary pattern (this almost never occurs).
Four Common Misinterpretations in Prostate Cancer Grading
|1. If a biopsied focus of cancer is small, it is Gleason grade 1 or 2, or "well-differentiated." ||Unlikely! Most cancers (over 80% in Gleason's original series) are primary grade 3. When the size is too small to call cancer, suspicious is the prudent default. Size of the focus of cancer has no bearing on Gleason grade at prostatectomy.|
|2. If a biopsied focus is suspicious for cancer, it is best called Gleason grade 1 or 2, or "well-differentiated." ||The prudent diagnosis in the absence of sufficient features for cancer is atypical small acinar proliferation (ASAP). Optimism seems naturally to lead one to consider low Gleason grade; but if there is cancer, it is usually moderately differentiated, since most peripheral zone cancers are moderately differentiated.|
|3. Confusing the large gland variant of Gleason grade 3 cancer with benign acini. ||Cancer acini occasionally are rounded, and medium to large, like benign acini. Look for microvacuolated cytoplasm, nuclear enlargement, and macronucleoli to diagnose cancer.|
|4. All cribriform acinar formations are Gleason grade 3. ||Some cribriform acinar formations are grade 4. These sieve-like spaces lose their round, rigid, punched-out contours, and elongate; the acini collapse into solid areas.|
|Needle core biopsy underestimates tumor grade in 33-45% of cases and overestimates grade in 4-32% (Kastendieck, 1980; Catalona et al., 1982; Lange et al., 1983; Garnett et al., 1984; Mills and Fowler, 1986; Epstein and Steinberg, 1990; Bostwick, 1994c; Spires et al., 1994). Grading errors are common in biopsies with small amounts of tumor and low grade tumor, and are probably due to tissue sampling error, tumor heterogeneity, and undergrading of needle biopsies. The accuracy of biopsy is highest for the primary Gleason pattern, but the secondary pattern also provides useful predictive information, particularly when combined with primary pattern to create the Gleason score. Gleason grading should be used for all needle biopsies (Bostwick, 1994b), even those with small amounts of tumor, according to the recommendations of Gleason (Gleason, 1992).|
|Kramer et al. compared Gleason score in 14 gauge needle biopsies with matched lymph node metastases, and found exact correlation in 17 of 42 cases (40%), + 1 in 32 of 42 cases (76%), and + 2 in 40 of 42 cases (95%) (Kramer et al., 1980; Kramer et al., 1981). The lack of a more anaplastic pattern in the metastatic deposits implies that factors other than loss of differentiation are responsible for the ability of cancer cells to metastasize (Brawn et al., 1990; Cumming et al., 1990).|
Reproducibility of Gleason Grading and Comparison with Other Grading Systems
|Interobserver and intraobserver variability limit the reproducibility of grading in the prostate as in other organs with their grading systems (Bain et al., 1982; Schroder et al., 1985a, 1985b, 1985c; Ten Kate et al., 1986; De Las Morenas et al., 1988; Gallee et al., 1990; Contra and Billis, 1991; Di Loreto et al., 1991; Gleason, 1992). The subjective nature of grading precludes absolute precision, no matter how carefully the system is defined, yet the significant correlation of prostatic adenocarcinoma grade with virtually every outcome measure attests to the predictive strength and utility of grading in the hands of most investigators. Gleason noted exact reproducibility of score in 50% of needle biopsies and + 1 score in 85%, similar to others (Gleason, 1992; Bain et al., 1982).|
|Some investigators question the utility of grading because of the significant incidence of interobserver variability (Bain et al., 1982; De Las Morenas et al., 1988; Di Loreto et al., 1991). One study found a high level of disagreement in grading among 3 pathologists evaluating 41 cases of well to moderately differentiated adenocarcinoma (Di Loreto et al., 1991). Another study compared the level of interoberver agreement with four grading systems in a consecutive series of 100 prostatic adenocarcinomas, and found the Gleason grading system to be the least reproducible, with complete agreement of score in only 66% of cases (De Las Morenas et al., 1988). To perform the analysis, the authors compressed the Gleason scores into three grade groups: 2-5, 6-7, and 8-10. Gallee et al. compared the prognostic accuracy of five grading systems (Broders, Gleason, M.D. Anderson, Mostofi, and Mostofi-Schroder), and found that the Gleason system had the lowest predictive ability for recurrence and death, whereas the Broders and Mostofi-Schroder systems had reasonable accuracy (Gallee et al., 1990). Conversely, another report compared the level of intraobserver agreement with the Gleason, Mostofi, and Bocking systems, and found no significant differences; further, the level of variability was unaffected by type of specimen or amount of tissue examined (Cintra and Billis, 1991). Despite questions of reproducibility, the collective experience supports the clinical utility of grading prostatic adenocarcinoma.|
|Using a variety of architectural and nuclear features, Bibbo et al. developed a Bayesian belief network for grading prostatic adenocarcinoma, and attained agreement with Gleason grade in 241 of 256 microscopic fields (Bibbo et al., 1990; Bibbo et al., 1993). Features used by the belief network included acinus formation, lumen area, acinar fusion, type of acinar fusion, acinar packing, acinar size, acinar uniformity, thickness of acinar epithelial layer, nuclear size, nuclear variability, nuclear shape, chromatin pattern, and nucleolar size. These authors noted that four diagnostic clues allowed unique mapping of Gleason primary patterns, and additional clues offered redundancy and robustness to the network.|
Proposed Modifications to Gleason Grading
|Morphometric nuclear grading|
|Grouping of grades|
|Amount of high grade cancer (Gleason patterns 4 and 5)|
|Cribriform pattern as 4 rather than 3|
|Gleason grading after therapy|
|Application of Gleason grade to Bladder cancer|
Nuclear and Nucleolar Grading
|Nuclear and nucleolar enlargement are important diagnostic clues for the diagnosis of malignancy. Morphometric methods allow objective evaluation of nuclear size, roundness, shape, chromatin texture, and other features. In an effort to create an objective method of grading prostatic adenocarcinoma, one study found that morphometric estimates of variation in nuclear size separated patients undergoing prostatectomy into two groups with differing survival rates (Blom et al., 1990). Other investigators have utilized morphometry to improve the predictive value of Gleason grading, but these methods are not used routinely (Diamond et al., 1982; Aragona et al., 1989; Robutti et al.,1989; Schultz et al., 1990;Irinopoulou et al., 1993).|
|Nuclear roundness has been the subject of considerable interest since the first report by Diamond et al. in 1982 (Diamond et al., 1982; Epstein et al., 1984; Mohler et al., 1987; Mohler et al., 1988a; Mohler et al., 1988b; Partin et al., 1989; Armas et al., 1991; Partin et al., 1992; Schaeffer et al., 1992). Average nuclear roundness accurately predicted prognosis in patients with untreated stage T1b (A2) prostatic adenocarcinoma and other clinical stage adenocarcinomas. However, many of these reports were limited by small sample size (less than 30 patients), use of the same patient cohort in multiple publications, failure to describe the morphologic variations and nuclear roundness extremes, and patient selection bias. Nuclear roundness failed to identify patients with tumor recurrence following radiation therapy except in those with well-differentiated adenocarcinoma (Schaeffer et al., 1992).|
|Nucleolar grading of prostatic adenocarcinoma has also been proposed, but has not been adopted (Grade 1: Large and prominent nucleoli in virtually every cell; Grade 2: Intermediate; Grade 3: Very small nucleoli which are difficult to find) (Myers et al., 1982).|
|Many authors have simplified the Gleason grading system by compressing the scores into groups, usually creating three groups: 2-3-4, 5-6-7, and 8-9-10 (De Las Morenas et al., 1988) Unfortunately, grade compression diminishes the statistical strength of grading (Gleason, 1992). Further, the choice of grouping is often problematic; the most important "cut point" is between Gleason score 6 and 7 due to the emergence of poorly differentiated adenocarcinoma (pattern 4) in score 7, yet many studies combine these scores. Gleason argued against grade compression except in studies with a small number of patients in which grouping is unavoidable; in such cases, a cutpoint between scores 6 and 7 is preferred (Gleason, 1992; Oesterling et al., 1987). The probability of lymph node metastases is significantly greater in patients with score 7 adenocarcinoma than in those with score 6 (Thomas et al., 1982; McNeal et al., 1990).|
Volume of High Grade Adenocarcinoma
|The volume of high grade adenocarcinoma appears to be an important prognostic factor; as tumor volume increases, the frequency and volume of high-grade tumor increases (McNeal et al., 1986; McNeal et al., 1990; Bostwick et al., 1993; Bostwick, 1994a). Gleason grade stratifies adenocarcinoma into three subgroups with different levels of aggressiveness; Gleason pattern 1 and 2 adenocarcinoma is almost always small, usually less than 1 cc, indolent, localized, and frequently located in the transition zone whereas pattern 3 adenocarcinoma is variable in size and very common. Pattern 4 and 5 adenocarcinomas are usually larger and more aggressive than lower grade tumors, and likely to extend beyond the prostate or metastasize (McNeal et al., 1990). One study of 209 radical prostatectomies from patients with clinical stage T1 and T2 adenocarcinomas reported that the volume of high grade adenocarcinoma (Gleason grades 4 and 5) had the highest predictive value for lymph node metastases, greater even than tumor volume (McNeal et al., 1990). Twenty-two of 38 patients (58%) with more than 3.2 cc of high-grade adenocarcinoma had pelvic lymph node metastases, compared with only 1 of 171 patients (0.6%) with smaller volumes of high-grade adenocarcinoma. The extent of solid undifferentiated carcinoma shows a strong correlation with tumor progression according to one report of 24 cases (Gaffney et al., 1992). Gleason score and percent of pattern 4 and 5 adenocarcinoma show a positive correlation with tumor volume (Bostwick, 1994a). In addition, poorly differentiated adenocarcinoma was the strongest predictor of tumor progression and cancer-specific survival in a series of 107 patients with clinically localized prostatic adenocarcinoma (Egawa et al., 1993). The cumulative data suggest that the volume of high-grade adenocarcinoma is of prognostic significance, refuting Gleason's contention that prostatic carcinoma behaves according to the average of histologic grades. However, many of these studies grouped the Gleason scores, raising questions of grade compression.|
|Histologic dedifferentiation of prostatic adenocarcinoma has been reported by numerous investigators, but these studies included only cases with more than one resection, probably selecting for adenocarcinomas which are more aggressive and thus more likely to require repeat operation (Brawn, 1983; Cumming et al., 1990; McNeal et al., 1990) Dedifferentiation occurs in 65% of repeat transurethral resctions (Brawn, 1983; Cumming et al., 1990). Dedifferentiation to high grade adenocarcinoma appears to be unusual in low-grade (Gleason patterns 1-3) and small volume (1 cc) adenocarcinoma, occurring in only 2.4% of patients in 7 years according to one study (Whittemore et al., 1991).|
Recommendations of WHO, 1999
|The Committee recommends that pathologists report Gleason score for all prostate specimens. Further, the relative percentage or proportion of high-grade cancer (Gleason primary pattern 4 and 5) be included. |
|A global Gleason score should be given for the entirity of multiple biopsies containing cancer (in addition to individual specimen grading).|
|Pathologists should pursue additional education, as appropriate, in understanding and using the Gleason system.|
EXTENT OF CANCER ON NEEDLE BIOPSY: RP DATA
Biopsy cancer volume depends on multiple
factors, including prostate volume, cancer volume, cancer distribution, number of biopsy cores obtained,
the cohort of patients being evaluated and the technical expertise of the person undertaking the biopsy
procedure. The combined results from multiple studies indicate that the biopsy extent of cancer is
somewhat predictive of cancer extent in radical prostatectomy specimens and should be reported, although
its predictive value for an individual patient is limited. Reliance upon this measure alone may often be
misleading. There is a fair to good correlation between amount of cancer reported in biopsies and that
subsequently found in radical prostatectomy specimens. This correlation is greatest for large cancers.
High cancer burden on needle biopsy is strongly suggestive of large volume high stage cancerr.
Low cancer volume on needle biopsy does not necessarily indicate low-volume low-stage
cancer in final prostatectomy specimens.
Cupp et al. found that patients with less than 30% of
needle cores replaced by cancer had a mean volume in the radical prostatectomy of 6.1 cc (range,
0.19-16.8 cc), indicating that the amount of tumor on transrectal needle biopsy was not a good predictor
of tumor volume. In another report, patients with less than 10% cancer in the biopsy had a 30% risk of
positive surgical margins, 27% risk of extraprostatic extension, and 22% risk of PSA biochemical
progression; these risks were higher in patients with more than 10% cancer. Patients with less than 3 mm
cancer and Gleason score 6 or less on needle biopsy had a 59% risk of cancer volume exceeding 0.5 cc.
Those with less than 2 mm of cancer had 26% risk of extraprostatic cancer, and those with less than 3 mm
had 52% risk. In another study, 66 patients diagnosed with a single microscopic focus of carcinoma on
biopsy were found to have grossly visible disease on prostatectomy specimens in 92% of cases. Rubin
reported that cancer volume on needle biopsy was predictive of extraprostatic extension, with the odds of
pT3 cancer increasing by a factor of 1.7 times with each 20% increase in cancer volume above 40% volume.
The CAP recommends that the volume of cancer in needle biopsy should be reported as the percentage of
tissue involved by cancer.
Cancer volume in biopsies was a strong predictor of biochemical failure. Similarly,
cancer volume in radical prostatectomy specimens was usually but not always predictive of cancer
recurrence. Accordingly, the CAP recommends that cancer volume be recorded in prostatectomy specimens,
although there is no accepted universal approach. Methods include computer-assisted morphometric
determination, simple measurement of length X height X section thickness of the cancer (some measure the
largest "index" focus, whereas others report the cumulative volumes), greatest cancer dimension , grid
method, and visual estimate of the percentage of cancer. Measurements performed on fixed tissue sections
may include a formalin shrinkage correction factor which varies from about 1.25 to 1.5, representing
tissue shrinkage of 18 to 33%; conversely, Schned and colleagues demonstrated that shrinkage correction
is unnecessary. Cancer volume is a critical element in definitions of clinically significant and
insignificant prostate cancer.
Vanishing Cancer Phenomenon
In some radical prostatectomy specimens, there is little or no residual cancer within the
specimen ("vanishing cancer phenomenon"). We recently reported that about 6 in 1,000 partially or
totally sampled radical prostatectomies (0.5%) had no residual cancer (stage pT0) among a series of 6,843
cases (Bostwick & Bostwick, in press). The incidence of this "vanishing cancer phenomenon" declined
more than ten-fold from 1966 to 1995, probably as a result of the substantial decline in the use of
transurethral resection of the prostate. We now encounter cases of no residual cancer in about 2 cases
per 1000 radical prostatectomies. This decline may be offset in recent years by two factors: (1) an
upswing in the number of patient receiving preoperative androgen deprivation therapy (or radiation
therapy) that causes apparent cancer volume reduction in some patients, although this trend was not
apparent in our study because such therapy was given only rarely to our patients; and (2) increasing
vigilance in screening demonstrates that prostate cancer is now being detected at smaller volume and
lower stage than ever before. None of our "vanishing cancer" patients developed clinical evidence of
cancer recurrence with a mean follow-up of almost 10 years (Bostwick & Bostwick). Further, those
that died of intercurrent disease had no evidence of cancer at the time of death. These cumulative data
strongly suggest that these patients are cured of cancer and no residual therapy is indicated.
The inability to identify residual cancer in radical prostatectomy specimens raises the
question of accuracy of the original diagnosis of cancer. In reports from Johns Hopkins Medical Center,
biopsies were overdiagnosed as cancer in 2 of 4 cases with no residual cancer after radical
prostatectomy1 and major changes in diagnosis occurred in
1.4% of referred cases following second opinion review; however, these results have not been confirmed by
other centers. Over-diagnosis of prostate cancer is also a concern, with an incidence of 21%
misdiagnosis in small foci in transurethral resection specimens between 1960 and 1970.
Genotypic analysis to verify patient identity in cases of "vanishing" cancer is becoming increasingly
popular and appears prudent to reassure patients (DG Bostwick, unpublished observations) and exclude the
possibility of improper patient identification. DNA "fingerprinting" can now be used to compare
formalin-fixed paraffin-embedded biopsies and prostatectomy tissues.
Substantial laboratory resources may be needed to identify minimal residual cancer, and even
exhaustive sectioning may fail. How many sections are reasonable to obtain in such cases? When can one
stop sectioning if no cancer is found? We believe that it is appropriate for the pathologist to submit
routine sections of the entire prostatectomy for histologic evaluation in such cases; however, after
submission and examination of the entire prostate, obtaining additional levels from paraffin blocks
and/or re-embedding all blocks (block-flipping) are probably not necessary, as any residual cancer at
that point is likely to be extremely small and of no clinical significance.
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