PROSTATIC

ADENOCARCINOMA,
PROSTATIC
INTRAEPITHELIAL
NEOPL ASIA, AND
INTRADUC TAL
CARCINOMA
Ming Zhou, MD, PhDa,b,c,d,e,*,
Cristina Magi-Galluzzi, MD, PhDa,b,c,d,e

KEYWORDS
 Prostatic adenocarcinoma  Prostatic intraepithelial neoplasia
 Intraductal carcinoma of the prostate

ABSTRACT PROSTATIC ADENOCARCINOMA

Prostatic Adenocarcinoma: Overview

P
rostate carcinoma (PCa) exhibits a wide
range of architectural and cytological fea-
tures. Gleason grading remains as one of
the most powerful histological prognostic
parameters. However, it has evolved considerably.
High-grade prostatic intraepithelial neoplasia
(high-grade PIN) is accepted as a precursor lesion
to PCa. Its detection in prostate biopsy is also
considered as a risk factor for detecting cancer
in subsequent biopsies. Such risk, however, has
significantly decreased in recent studies. Intraduc-
tal carcinoma of the prostate (IDC-P) represents
the intraductal spread of invasive cancer and
constitutes a poor histologic parameter. This arti-
cle reviews the key histological features of PCa,
high-grade PIN and IDC-P, as well as the Gleason
grading system that was most recently updated in
2005.
PCa is the most common noncutaneous malig-
nancy in American men and is the third most
common cancer in men worldwide.1 In 2008
there were an estimated 186,320 newly diag-
nosed cases and 28,860 deaths, which account
for approximately 10% of all cancer deaths in
men in United States.2 The prevalence rises dra-
matically with age. The disease is exceedingly
rare before the age of 45 years and is uncommon
before age 50 years. The prevalence is more than
45 times greater in men over 65 years than in
those under 65 years.3 Multiple genetic and envi-
ronmental factors have been implicated in the
prostate carcinogenesis.4 Most PCa cases are
asymptomatic and currently are detected by
serum prostate-specific antigen (PSA) screening
and digital rectal examination. About three

a
Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA
surgpath.theclinics.com

b
Glickman Urologic and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA
c
Department of Cancer Biology, Cleveland Clinic, Cleveland, OH, USA
d
Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA
e
Department of Anatomic Pathology, Cleveland Clinic, L25, 9500 Euclid Avenue, Cleveland, OH 44195, USA
* Corresponding author. Department of Anatomic Pathology, Cleveland Clinic, L25, 9500 Euclid Avenue,
Cleveland, OH 44195.
E-mail address: zhoum@ccf.org (M. Zhou).

Surgical Pathology 1 (2008) 43–75

doi:10.1016/j.path.2008.08.001
1875-9181/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.
44 Zhou & Magi-Galluzzi

fourths of cases arise in the peripheral zone, and

some can result in abnormal digital rectal exam- Key Pathologic Features
inations. Rarely, PCa can lead to urinary obstruc- PROSTATIC ADENOCARCINOMA
tion when large tumor arises in the transition
zone, extends into the transition zone from the
Gross appearance
peripheral zone, or invades the bladder neck.
Locally aggressive PCa that involves the bladder PCa appears firm, solid, white-gray to yellow-
orange, in contrast to tan, spongy benign pros-
and rectum can cause hematuria, rectal bleeding,
tatic tissue. Cancer detected by PSA screening
or obstruction. Rarely, patients present with
often is not grossly visible.
symptoms and signs that are related to PCa
metastatic to other body sites, most commonly Architectural features
bone, regional lymph nodes, lung, and brain. Haphazard glandular arrangement
Infiltrative growth
Prostatic Adenocarcinoma:
Less-differentiated glands with cribriform or
Gross Features fused glands, cords, sheets, or single tumor cells
In contrast to benign prostate tissue that appears Typically small glands with straight luminal
tan and spongy, grossly evident PCa is firm, solid, borders
and ranges in color from white-gray to yellow-or-
Cytologic features
ange.5 With PSA screening, small tumors of low
stage are being detected more often, and PCa Relatively uniform cytologic features
becomes less visible grossly. Pale to amphophilic cytoplasm
No lipofuscin pigment
Prostatic Adenocarcinoma:
Nuclear features
Microscopic Features
Nuclear enlargement
PCa has a constellation of architectural, cytoplas-
mic, nuclear, and intraluminal features.6,7 Hyperchromasia
Variably prominent nucleoli
Architecture Mitosis and apoptotic bodies rarely seen
PCa can exhibit one or several architectural pat- Intraluminal features
terns that are significantly different from those of Crystalloids
benign glands. The most characteristic pattern is
the infiltrative pattern with cancer glands situated Blue mucin
between or on both sides of benign glands Pink amorphous secretion
(Fig. 1A). This pattern indicates the invasive nature Cancer-specific features
of PCa, because PCa in general does not induce
Mucinous fibroplasia (collagenous micronodules)
the desmoplastic stromal response characteristic
of other types of cancer. In contrast, a benign pro- Glomeruloid formation
cess usually maintains a lobular architecture. Perineural invasion
Cancer glands can also form a focus with
closely packed, pale, small glands (Fig. 1B). The
focus often is well circumscribed without an infil-
trative pattern. In such cases, the differential diag-
nosis always should include a PCa that arises in
the anterior or transition zone and adenosis (atyp- PCa, typically in high-grade cancer and following
ical adenomatous hyperplasia). The cancer glands treatment, PCa in general lacks basal cells. The
also can display a haphazard growth and dissect lack of a basal cell layer is not always reliably ob-
stroma and smooth muscle bundles without served on hematoxylin and eosin slides but can
accompanying benign glands (Fig. 1C). They also be confirmed with immunostaining for basal cells,
can form large cribriform structures with irregular including high-molecular-weight cytokeratin and
and infiltrative borders (Fig. 1D). Finally, they can P639 (Fig. 2).
grow in single cells or cords of cells (Fig. 1E).

Absence of Basal Cells Cytoplasm

8
The absence of basal cells is the hallmark of PCa . In contrast to benign glands that have irregular and
Although basal cells may be detected rarely in undulating luminal borders, PCa glands are
 Prostatic Adenocarcinoma 45

Fig. 1. Architectural pat-

terns of PCa. (A) Cancer
glands display an infiltra-
tive growth pattern with
malignant glands situ-
ated between or flanking
benign glands. (B) They
also can form a focus
with closely packed,
pale, and small glands.

smaller and have straight luminal borders. They
may have amphophilic cytoplasm that is evident
even at low magnification (Fig. 3). Low-grade
PCa, however, often has pale, clear cytoplasm
similar to that of benign glands. PCa typically lacks
lipofuscin pigment that can be found in benign
glands.
Nuclei
PCa invariably displays atypical nuclear features
distinct from the surrounding benign glands, in-
cluding nuclear enlargement and prominent
nucleoli (Fig. 4). Some PCas may lack prominent
nucleoli but have enlarged and hyperchromatic
nuclei. Mitoses and apoptotic bodies, which are
found rarely in benign glands, are somewhat
more common in PCa, although they still are not
commonly seen in malignant glands. Cancer nu-
clei, even in poorly differentiated ones, show rela-
tive uniformity in size and shape.
Intraluminal Contents
Crystalloids, dense eosinophilic crystal-like struc-
tures found within the glandular lumens (Fig. 5A),
46 Zhou & Magi-Galluzzi

Fig. 1. (C) The cancer

glands display haphazard
growth and dissect
stroma and smooth mus-
cle bundles without ac-
companying benign
glands. They also can
form (D) large cribriform
structures with irregular
and infiltrative borders
or, as shown on the fol-
lowing page, grow in sin-
gle cells or cords of cells.

are more common in cancer than in benign glands,
although they also are found frequently in adenosis.
Intraluminal pink, amorphous, dense secretions
(Fig. 5B) and blue-tinged mucin (Fig. 5C) are addi-
tional findings seen preferentially in PCa. In con-
trast, corpora amylacea are common in benign
glands and are not seen in PCa.
Tumor Stroma
Ordinary PCa does not elicit a stromal inflamma-
tory or desmoplastic response. Ductal prostate
adenocarcinoma, however, may induce such stro-
mal reactions with fibrosis and hemosiderin-laden
macrophages.
Cancer-Specific Histologic Features
Three histologic features are considered specific
for PCa, because they have not been described
in benign glands. Mucinous fibroplasia, or collage-
nous micronodules, occurs as delicate fibrous tis-
sue with ingrowth of fibroblasts within or adjacent
to cancer glands (Fig. 6A). Glomeruloid formation
 Prostatic Adenocarcinoma 47

Fig. 1. (E) The cancer

glands can grow in single
cells or cords of cells.

is created by intraluminal proliferation of cancer
cells and often is surrounded by a crescentic
space, superficially resembling a renal glomerulus
(Fig. 6B). Perineural invasion represents tight
circumferential or nearly circumferential encircling
of a nerve by cancer cells (Fig. 6C). Occasionally,
intraneural invasion of cancer cells can be seen
also. The cancer cells in perineural or intraneural
invasion may have paradoxically bland nuclear
features and may mimic benign glands. Benign
prostatic glands occasionally can lie adjacent to
and press on a nerve, a finding termed ‘‘perineural
indentation by benign prostatic glands,’’ but
benign glands do not encircle a nerve tightly.

Fig. 2. Lack of basal cells

in prostate carcinoma
confirmed by the immu-
nostain for a basal cell
marker P63.
48 Zhou & Magi-Galluzzi
Prostatic Adenocarcinoma:
Differential Diagnosis
PCa should be differentiated from many other be-
nign and malignant prostate lesions (Table 1) that
may cause architectural and/or cytologic atypia
and therefore may be mistaken for cancer by un-
wary eyes. In many instances the differential is
with normal prostatic and nonprostatic structures,
including seminal vesicles/ejaculatory duct epithe-
lium, Cowper’s gland, paraganglia, and meso-
nephric duct remnants. Benign prostatic lesions
such as inflammation, atrophy (simple atrophy,
partial atrophy, and postatrophic hyperplasia),
metaplasia (urothelial, squamous, and mucinous),
basal cell hyperplasia, benign prostatic hyperpla-
sia, and benign prostatic glands with radiation
and hormonal treatment effects can simulate
PCa to varying degrees. On the other hand, PCa
may exhibit only mild architectural or cytologic aty-
pia, making it difficult to distinguish between ma-
lignant and benign prostate conditions. For
example, a well-differentiated Gleason score 2 to
4 PCa, although rarely encountered, always
should be differentiated from adenosis. Cribriform
PCa should be distinguished from benign cribri-
form hyperplasia or cribriform high-grade PIN.
Atrophic and foamy gland PCa may be confused
with benign atrophy and xanthoma, respectively.
Pseudohyperplastic PCa shares some architec-
tural features with benign prostatic hyperplasia, al-
though the former invariably has significant nuclear
atypia. Careful evaluation of the architectural and
Differential Diagnosis
PROSTATIC ADENOCARCINOMA
1. Normal prostatic/nonprostatic tissue (semi-
nal vesicle/ejaculatory duct, verumontanum
glands, Cowper’s glands, paraganglia, meso-
nephric remnants)
2. Benign lesions (atrophy, partial atrophy,
postatrophic hyperplasia, urothelial/squa-
mous metaplasia, basal cell hyperplasia,
adenosis, sclerosing adenosis, inflammation,
nonspecific granulomatous prostatitis, be-
nign prostatic hypertrophy)
3. Benign prostatic tissue with treatment effect
(radiation atypia)
4. High-grade PIN
5. Other malignant lesions of non-acinar type
(urothelial, small cell, basal cell, and squa-
mous cell carcinoma)
cytologic features and prudent use of basal cell
markers and a-methylacyl coenzyme A racemase
(AMACR) should lead to a correct diagnosis.
PCa also should be differentiated from other
non-acinar adenocarcinoma. Rarely, the prostate
gland can be involved by primary urothelial carci-
noma, small cell carcinoma, mucinous carcinoma,
and signet-ring cell carcinoma. Such a diagnosis
should be made only after a metastasis from other
Fig. 3. PCa glands with
amphophilic cytoplasm.

Fig. 4. PCa cells with en-
larged nuclei and promi-
nent nucleoli.
sites has been diligently excluded, however,
because metastasis is far more common than
non-acinar adenocarcinoma. Small cell carci-
noma, urothelial carcinoma, and lymphoma should
always be considered and ruled out for a high-
grade PCa with a solid growth pattern and little
or no glandular differentiation.
Prostatic Adenocarcinoma: Diagnosis
Many histologic features are important for the
diagnosis of PCa, but only three—collagenous mi-
cronodules (mucinous fibroplasia), glomerulation,
and perineural invasion—are diagnostic of PCa.
Furthermore, these three features are present
only infrequently in PCa diagnosed by prostate bi-
opsy. Therefore in most cases the diagnosis of
cancer relies on other histologic features. These
histologic features are categorized as major diag-
nostic criteria, which are present in most cases of
PCa, and minor diagnostic criteria, which are
present in only a minority of cases (Box 1).7,10,11
None of these features, however, is specific and
diagnostic for PCa. Therefore, a definitive cancer
diagnosis requires a constellation of major and
minor criteria.
Before a definitive cancer diagnosis is estab-
lished, one must rule out any noncancerous
Prostatic Adenocarcinoma 49
conditions that may cause architectural and cyto-
logic atypia (Box 2).12–16
Benign glands with intense inflammation, espe-
cially acute inflammation, can cause both archi-
tectural and cytologic atypia resembling that
seen in cancer. Benign glands with atrophic cyto-
plasm, including partial atrophy and postatrophic
hyperplasia, can present as small crowded glands
with nuclear atypia, although the degree of the
nuclear atypia often is mild and prominent nucleoli
should be absent. When the atypical glands form
a relatively well-circumscribed focus, adenosis
always should be ruled out before the diagnosis
of well-differentiated, Gleason grade 5 or less
cancer is rendered. Last, a small focus of atypical
glands immediately adjacent to high-grade PIN
may represent a focus of microinvasive cancer17
or tangential/out-pouching from the high-grade
PIN glands (Fig. 7).
The diagnostic criteria do not include the quan-
titative threshold for the number of glands required
to make a cancer diagnosis. Most urologic pathol-
ogists require at least three glands to make
a cancer diagnosis with confidence,10 although
a cancer diagnosis can be made in the presence
of fewer than three neoplastic glands if other char-
acteristic architectural and cytologic features of
PCa are present.
50 Zhou & Magi-Galluzzi

Fig. 5. (A) PCa with crys-

talloids found within
the glandular lumina.
(B) Intraluminal pink,
acellular, dense secre-
tions are common
findings.

A practical approach for diagnosis of PCa is
shown in Fig. 8. A cancer diagnosis requires that
all three criteria be satisfied, including the
presence of architectural atypia, the presence of
cytologic atypia, and the exclusion of benign con-
ditions that may cause such architectural and
cytologic atypia. If any one of these three criteria
is not met, a cancer diagnosis cannot be made,
and additional studies, including immunohisto-
chemistry and deeper sections, should be
performed to try to arrive at a more definitive
diagnosis.
Prostatic Adenocarcinoma: Prognosis
The clinical outcomes for patients who have PCa
are highly variable and depend on many host and
tumor parameters and on response to therapy.
Several clinicopathologic parameters, including
preoperative serum PSA, Gleason grade, TNM
stage, and surgical margin status, have been

Fig. 5. (C) PCa with blue-
tinged mucin also are
common findings.
proven to have prognostic significance and to be
useful in clinical management. Other factors, in-
cluding DNA ploidy, tumor volume, and histologic
subtypes, have been studied extensively. Their
importance, however, remains to be validated in
large multicenter trials. Some other factors,
including perineural invasion, neuroendocrine dif-
ferentiation, microvessel density, nuclear features
other than ploidy, proliferation markers, and
a variety of molecular markers, have not been
studied sufficiently to demonstrate their prognos-
tic value.
Pitfalls
PROSTATIC ADENOCARCINOMA
! Cancer-specific histologic features (mucinous
fibroplasia, glomerulation, and perineural
invasion) infrequently are present in prostate
biopsies; therefore in most cases a cancer
diagnosis requires a constellation of architec-
tural and cytologic features and the exclusion
of benign conditions that may cause architec-
tural and cytologic atypia.
Prostatic Adenocarcinoma 51
PROSTATIC ADENOCARCINOMA:
GLEASON GRADING SYSTEM
Based on the architectural features of PCa, the
Gleason grading system was proposed first by
Dr. Donald Gleason in 1960s.18,19 In this system,
PCa is categorized into one of five patterns (Glea-
son patterns 1–5) representing a morphologic con-
tinuum of decreasing glandular differentiation
(Fig. 9A). Another unique feature of this system is
that instead of assigning a single worst grade,
the most prevalent and second most prevalent
patterns are summed to obtain the final Gleason
grade. The Gleason grading system currently is
the most widely used system and has been
endorsed by the World Heath Organization.
Numerous reports have confirmed the significance
of Gleason grade in predicting outcome in patients
undergoing various treatment modalities, includ-
ing surveillance, radical prostatectomy, and
radiation therapy.20–24 In patients receiving neoad-
juvant or adjuvant hormonal therapy, the Gleason
grade also has been found to be an independent
predictor of biochemical failure.20
The Gleason grading system has evolved signif-
icantly since its inception 40 years ago. It was
modified most recently in 2005 following the
recommendations of the International Society of
Urological Pathology.25 There are several argu-
ments for a contemporary approach to the Glea-
son grading system, including changed clinical
52 Zhou & Magi-Galluzzi

Fig. 6. PCa-specific fea-

tures. (A) Mucinous fi-
broplasias consists of
delicate fibrous tissue
with ingrowth of fibro-
blasts within or adjacent
to cancer glands. (B) Glo-
meruloid formation is
formed by intraluminal
proliferation of malig-
nant cells and often is
surrounded by a crescen-
tic space.

characteristics of PCa resulting from wide-spread PCa Gleason Pattern 1

PSA screening and transrectal ultrasound-guided
needle biopsies, improved pathologic diagnosis
resulting from the use of immunohistochemical
markers, and the recognition of new histologic
variants and tertiary Gleason patterns. The new
Gleason grading scheme is summarized in
Fig. 9B. The significant changes include a more
stringent definition of Gleason pattern 3 cribriform
glands and the grading of poorly formed glands
as pattern 4.
Gleason pattern 1 consists of well-circumscribed
nodules of closely packed but separate, uniform,
round to oval, medium-sized acini (Fig. 10A).
With the use of basal cell immunohistochemistry,
however, most cases that once would have been
diagnosed as Gleason score 1 1 1 5 2 now are
identified as adenosis. Therefore, except for ex-
tremely rare exceptions, Gleason pattern 1 is
a grade that should not be diagnosed regardless
of the types of the specimen.

Fig. 6. (C) In perineural
invasion, cancer glands
entirely or partially encir-
cle a nerve.
PCa Gleason Pattern 2
In Gleason pattern 2 the cancer glands form fairly
circumscribed nodules, but there may be minimal
infiltration at the periphery (Fig. 10B). The cancer
glands demonstrate moderate variation in size and
shape, with a looser arrangement and more atypia
in cancer cells than seen in Gleason pattern 1.
Cribriform glands are not permitted in Gleason pat-
tern 2. Gleason pattern 2 is found occasionally in
transurethral resection of the prostate and in
multifocal low-grade cancer within the radical pros-
tatectomy specimens. With needle biopsy, a diag-
nosis of Gleason grade 2 1 2 5 4 is rarely
possible, because one must visualize the entire
cancer nodule that often is sampled only partially
by prostate biopsy. Because of poor reproducibility,
lack of correlation between biopsy and prostatec-
tomy Gleason grade, sampling error, and potential
misunderstanding of the clinical implications,
a Gleason grade of 3 or 4 should be stated rarely,
if ever, in needle biopsy.
PCa Gleason Pattern 3
In Gleason pattern 3, there are discrete glandular
units, typically smaller glands than in Gleason pat-
tern 1 or 2, with infiltrates in and among benign
glands (Fig. 10C). The cancer glands typically
vary markedly in size and shape. Only cribriform
glands similar in size to normal glands and with
smooth noninfiltrative contours are considered as
Gleason pattern 3 (Fig. 10D). Gleason pattern 3
is the most common grade encountered in needle
biopsy specimens.
Prostatic Adenocarcinoma 53
PCa Gleason Pattern 4
Fused glands, large or irregular cribriform glands,
and ill-defined glands with poorly formed glandular
lumina are graded as Gleason pattern 4 (Fig. 10E
and F). Hypernephroid morphology in which fused
glands have clear or very pale cytoplasm and su-
perficially resemble clear cell renal cell carcinoma
is encountered rarely. Gleason pattern 4 consti-
tutes an important clinical decision-making point,
because the presence of any Gleason pattern 4
signals clinically significant disease, and a different
therapeutic modality may be indicated.
PCa Gleason Pattern 5
Gleason pattern 5 is graded when there is essen-
tially no glandular differentiation, and tumor is
composed of solid sheets, cords, or single cells
(Fig. 10G and H). Comedocarcinoma with central
necrosis surrounded by papillary, cribriform, or
solid masses also is graded as pattern 5 (Fig. 10I).
PROSTATIC INTRAEPITHELIAL NEOPLASIA
Prostatic Intraepithelial
Neoplasia: Overview
‘‘Prostatic intraepithelial neoplasia’’ is the pre-
ferred diagnostic term for a putative premalignant
proliferation of atypical epithelial cells within the
pre-existing prostatic ducts and acini.26 It can be
diagnosed only by histology, because there are
no specific clinical or radiologic findings, and
serum PSA is not elevated.
54 Zhou & Magi-Galluzzi
Box 1
Histologic criteria for diagnosis of prostate
carcinoma
Major criteria
Architectural: infiltrative growth, small
crowded glands, confluent/irregular cribriform
glands, single/cords of cells
Loss of basal cells
Nuclear atypia: nuclear and nucleolar enlarge-
ment, hyperchromasia
Minor criteria
Intraluminal blue mucin
Pink amorphous secretions
Mitotic figures and apoptotic bodies
Crystalloids
Adjacent high-grade PIN
Amphophilic cytoplasm
PIN can be categorized as low grade and high
grade based on the severity of architectural and
cytologic atypia. The prevalence of high-grade
PIN increases with age. The incidence of high-
grade PIN in prostate needle biopsies varies from
0% to 24.6% with a mean of 7.7% (median,
5.2%), although it is present in almost all radical
prostatectomies.
Prostatic Intraepithelial Neoplasia:
Microscopic Features
PIN glands have architecture similar to that of the
adjacent benign glands but appear darker because
of their higher nuclear density and increased cyto-
plasmic eosinophilia or amphophilia (Fig. 11A).
Low-grade PIN shows crowding of luminal secre-
tory cells and irregular nuclear spacing and strati-
fication. Nuclei are enlarged and vary in size,
although the chromatin appears normal and nucle-
olar prominence is rare or absent. The basal cell
layer is intact. It is difficult to distinguish
Box 2
Histologic features suggesting a diagnosis other
than prostate carcinoma
Atypia associated with inflammation
Atrophic cytoplasm
Small glands merging with benign glands with
indistinct cytoplasm and cytology
Presence or mixture of adjacent PIN
Key Pathologic Features
PROSTATIC INTRAEPITHELIAL NEOPLASIA
1. Appearance: high-grade PIN with luminal cell
crowding, irregular spacing, and ‘‘piling-up’’
with chromatin hyperchromasia and clump-
ing, and prominent nucleoli
2. Architectural patterns: flat, tufting, micro-
papillary, and cribriform
3. Histologic variants: signet-ring, mucinous,
inverted, and small cell neuroendocrine
carcinoma
4. Staining for basal cells may be complete, dis-
continuous, or occasionally absent. AMACR
is detected in majority of high-grade PIN.
reproducibly low-grade PIN from normal or hyper-
plastic epithelium; therefore, a diagnosis of low-
grade PIN is not recommended.
Cytologically individual cells in high-grade PIN
are enlarged more uniformly with less nuclear var-
iation than seen in low-grade PIN. Many cells show
large and prominent nucleoli and hyperchromatic
and clumpy chromatin (Fig. 11B), similar to that
seen in PCa. The basal cell layer often is discontin-
uous and occasionally can be absent.
There are four major structural patterns
(Fig. 12A–D),27 and several minor variations for
high-grade PIN, including tufting (56%), micropa-
pillary (29%), flat (15%), and cribriform (0%–5%).
Uncommon to rare variants include inverted PIN,
in which nuclei are aligned along the luminal
surface rather than the basal aspect. The cells
lining the high-grade PIN glands have nucleome-
galy, coarse and hyperchromatic chromatin, and
prominent nucleoli. Occasionally, they may exhibit
neuroendocrine, signet-ring cell, and other fea-
tures.28,29 These structural patterns are mentioned
for diagnostic consideration and in general do not
have any clinical significance.
Prostatic Intraepithelial Neoplasia:
Differential Diagnosis
Several histologic variations of normal prostatic
glands and structures, including central zone
glands and seminal vesicle or ejaculatory duct ep-
ithelium, should be recognized and distinguished
from high-grade PIN. Prominent nucleoli are not
present in these structures. High-grade PIN may
involve central zone glands, however.
Benign, non-neoplastic conditions, including
prostate glands and ducts adjacent to inflammation

Differential Diagnosis
PROSTATIC INTRAEPITHELIAL NEOPLASIA
 Prostatic central zone glands
 Seminal vesicle/ejaculatory duct epithelium
 Reactive atypia caused by inflammation,
infarction, or radiation
 Metaplasia (transitional cell, squamous cell)
 Hyperplasia (clear cell cribriform hyperplasia,
basal cell hyperplasia)
 PCa with cribriform pattern
 Ductal adenocarcinoma
 Urothelial carcinoma
or infarction, squamous and transitional cell
metaplasia, and benign glands after irradiation,
also may cause architectural and cytologic aty-
pia that may be mistaken for high-grade PIN.
Basal cell hyperplasia often appears as small
and solid nests, although some may retain lu-
mens, in contrast to medium- to large-caliber
glands affected by high-grade PIN. When prom-
inent nucleoli are present, but the nucleoli are in
the basal cells rather than in secretory cells, the
term ‘‘atypical basal cell hyperplasia’’ is used.
Fig. 7. High-grade PIN
with adjacent small focus
of atypical glands. Adja-
cent to a high-grade PIN
gland are several small
glands suspicious for can-
cer. They may represent
a minute focus of inva-
sive prostate carcinoma
or tangential sectioning/
outpouching from the
high-grade PIN gland.
Prostatic Adenocarcinoma 55
One often can find secretory cells on top of
the hyperplastic basal cells. Immunohistochemi-
cally, basal cell hyperplasia is positive for basal
cell markers; the apical secretory cells are not,
and only residual basal cells are highlighted by
such stains in high-grade PIN.
Although exhibiting cribriform architecture at
low magnification, clear cell cribriform hyperplasia
does not display cytologic atypia and frequently
has a prominent basal cell layer that forms a collar-
ette around the gland.
Differentiating high-grade PIN from invasive
cribriform PCa and IDC-P is more problematic. In-
vasive cribriform PCa lacks basal cell lining. The
most salient histologic feature that distinguishes
IDC-P from high-grade PIN is the presence of
multiple cribriform glands with prominent nuclear
atypia and comedonecrosis. Occasionally, ductal
adenocarcinoma may arise in peripheral zone, or
ordinary acinar PCa may have focal features
resembling ductal adenocarcinoma. In addition,
ductal adenocarcinoma usually retains basal cell
layers. The papillae in ductal adenocarcinoma
have true fibrovascular cores, however, and cells
may show significant nuclear atypia with a high mi-
totic rate and extensive necrosis, features uncom-
mon in high-grade PIN. When involving prostatic
ducts and acini, urothelial carcinoma replaces the
ductal–acinar epithelium with predominantly solid,
highly atypical, and mitotically active neoplastic
cells. The cytoplasm of these cells is dense or
56 Zhou & Magi-Galluzzi
Architectural Atypia
Cytological Atypia
Rule out benign conditions that may cause architectural/cytological atypia
Any 1 absent
All 3
present
Atypical glands suspicious for PCa (ATYP)
PCa Additional study (deeper sections, IHC)
PCa Benign
‘‘hard’’ and may show squamous differentiation,
compared with the granular cytoplasm of PIN.
Immunohistochemically, urothelial carcinoma cells
are positive for cytokeratin K903 and P63 but are
negative for prostate-specific markers such as PSA.
Prostatic Intraepithelial Neoplasia: Diagnosis
PIN glands retain benign architecture but appear
basophilic at scanning power because of cyto-
plasmic amphophilia, nuclear crowding, and hy-
perchromasia. Several studies have shown that
good distinction between low-grade and high-
grade PIN can be achieved. The prominent nucle-
oli are the best discriminator between the two.
There is no consensus as to what constitutes
prominent nucleoli, but the presence of distinct
nucleoli visualized at 20 magnification in even
a few cells qualifies as prominent nucleoli, and
therefore a diagnosis of high-grade PIN can be
established. In contrast, low-grade PIN may
have nuclear enlargement and stratification, but
at higher magnification it has only inconspicuous
or tiny nucleoli. In the absence of prominent
nucleoli, the presence of mitosis and significant
nuclear pleomorphism also can be used to diag-
nose high-grade PIN.
There are two reasons that low-grade PIN
should not be diagnosed in prostate biopsy. First,
the finding of low-grade PIN in a needle biopsy is
not associated with an increased risk for detecting
cancer in subsequent biopsies. Cancer is found in
approximately 18% of patients who undergo re-
peat biopsy after a first biopsy shows low-grade
PIN. On the other hand, PCa is found in 20% of
patients who undergo a repeat biopsy after a first
Fig. 8. A practical ap-
proach for diagnosis of
prostate carcinoma in
prostate biopsy. ATYP,
atypical glands suspi-
cious for PCa; IHC,
immunohistochemistry.
ATYP
biopsy shows benign prostatic tissue. Therefore,
the finding of low-grade PIN is not associated
with an increased risk for detecting cancer in
subsequent biopsies.30–33 Second, the diagnostic
reproducibility for low-grade PIN is poor, even
among expert uropathologists.6
Prostatic Intraepithelial Neoplasia:
Immunohistochemistry
High-grade PIN is positive for pan-cytokeratins
(AE1/3 and Cam5.2) and for the prostate-specific
markers PSA and prostate-specific acid phospha-
tase. Stains for basal cells demonstrate complete,
discontinuous, or even occasionally absent basal
cell layers. Expression of AMACR is detected in
most high-grade PIN.
Prostatic Intraepithelial Neoplasia: Prognosis
The importance of recognizing high-grade PIN in
needle biopsy lies in its association with PCa in
Pitfalls
PROSTATIC INTRAEPITHELIAL NEOPLASIA
! The cancer risk associated with high-grade PIN
has decreased to 25% in recent studies, similar
to that associated with an initial benign diag-
nosis and lower than the previously reported
cancer risk. Therefore, stringent diagnostic cri-
teria for high-grade PIN should be employed.
! Basal cells occasionally may be absent in high-
grade PIN, especially in small focus.
 Prostatic Adenocarcinoma 57

Fig. 9. Gleason grading

system for prostate carci-
noma. (A) Original stan-
dardized drawing for
grading prostate carci-
noma. (From Gleason DF.
Classification of prostatic
carcinomas. Cancer Che-
mother Rep 1966;50:125–
28.)

repeat biopsy.11,17,34,35 Therefore, patients who
have a diagnosis of high-grade PIN in needle
biopsy are advised to undergo repeat biopsies.
The cancer risk in recently performed studies
varies widely from that in studies that were per-
formed in the early 1990s. In studies performed
in the early 1990s, the average risk of cancer asso-
ciated with high-grade PIN was 36%. In studies
performed between 1995 and 1999, the risk drop-
ped to 28%. In studies performed after 1999, the
risk decreased further to 21%.36 In contemporary
series, the cancer risk associated with high-grade
PIN is around 25%, only slightly higher than that
associated with a benign diagnosis.11 Most stud-
ies comparing the cancer risk following a needle
biopsy diagnosis of high-grade PIN and the cancer
risk following a benign needle biopsy diagnosis
show no difference between the two groups. Clin-
ical variables, including PSA level, PSA velocity,
findings on digital rectal examination or transure-
thral resection, and a family history of PCa, do
not seem to predict the cancer risk associated
with a diagnosis of high-grade PIN on prostate bi-
opsy. Histologic variables, such as the number of
58 Zhou & Magi-Galluzzi

Fig. 9. (B). Modified

Gleason grading system.
(From Epstein JI, Alls-
brook WC Jr, Amin MB,
et al. The 2005 Interna-
tional Society of Urologi-
cal Pathology (ISUP)
Consensus Conference
of Gleason Grading of
Prostatic Carcinoma. Am
J Surg Pathol 2005;
29(9):1228–42; with
permission.)
 Prostatic Adenocarcinoma 59

Fig. 10. Gleason grading

of PCa. (A) Pattern 1: can-
cer glands, which are
closely packed but are
separated and are of in-
termediate size and are
similar in size and shape,
form a well-circum-
scribed nodule. (B) Pat-
tern 2: cancer glands are
medium sized with some
degree of variation in
size and shape, have
a looser arrangement,
and form a circumscribed
nodule with occasional
peripheral infiltration.
60 Zhou & Magi-Galluzzi

Fig. 10. (C) Pattern 3: the

cancer glands infiltrate
between the adjacent
benign glands. Cribri-
form glands are small
and have smooth, round
contours. (D) Pattern 4:
cribriform glands are
large and have irregular
contours and jagged
edges.
 Prostatic Adenocarcinoma 61

Fig. 10. (E) Poorly

formed glands still have
glandular configuration
but have ill-formed glan-
dular lumens. (F) Pattern
5: cancer cells form
62 Zhou & Magi-Galluzzi

Fig. 10. (G) solid sheets,

(H) strands, or single cells
invading the stroma.
 Prostatic Adenocarcinoma 63

Fig. 10. (I) Comedonec-

rosis is present.

cores involved by high-grade PIN and the extent of INTRADUCTAL CARCINOMA

the involved cores and the type of high-grade PIN, OF THE PROSTATE
as well as molecular and genetic attributes, do not
influence the cancer risk in most studies. In a re- Intraductal Carcinoma,
cent review article, the authors recommend that Prostate: Overview
patients do not need a routine biopsy within
It has been recognized that some ‘‘invasive,’’
a year following the diagnosis of high-grade
Gleason pattern 3 to 5 prostatic adenocarcinomas
PIN,11 and the patient and the treating physician
actually have basal cell layers seen on light micro-
should decide whether repeat biopsies should be
scopic examination or, more commonly, on immu-
performed beyond 1 year from the diagnosis of
nostains for basal cells. In the past, these lesions
high-grade PIN. Several recent studies, however,
were diagnosed variably as high-grade PIN or as
suggest that in certain clinical scenarios high-
ductal-type prostatic adenocarcinoma. McNeal
grade PIN confers a much higher cancer risk
and colleagues39 first suggested that the finding
than that reported in the literature. For example,
may represent an aggressive form of prostatic
one study found a 39% risk of finding PCa on re-
adenocarcinoma, because it almost never is seen
peat biopsies obtained after an initial diagnosis
in the absence of an invasive component. If
of widespread high-grade PIN that involved four
present, the invasive component almost always is
or more biopsy cores and supported the need for
high grade and has large tumor volume. The term
repeat biopsy in this subset of patients.37 Another
‘‘intraductal prostatic carcinoma’’ was proposed.
example is a prostate biopsy with a diagnosis of
atypical glands suspicious for cancer (ATYP);
repeat biopsies will detect cancer in 45% to 60% Intraductal Carcinoma, Prostate:
of patients with such a diagnosis. In a recent study Microscopic Features
by Ramirez and colleagues,38 however, the risk of The enlarged prostate acini and ducts are filled
cancer in patients who had both ATYP and high- with cytologically malignant cells. The basal cell
grade PIN was 57%, compared with 40% in layers are present or at least are partially pre-
patients who had only ATYP. served and can be confirmed by immunostains
64 Zhou & Magi-Galluzzi
Key Pathologic Features
INTRADUCTAL CARCINOMA OF THE PROSTATE
1 The prostate acini are enlarged, and the
ducts are filled with cytologically malignant
cells with complete or partial preservation
of basal cell layers.
2 There are three major histologic patterns:
trabecular, cribriform, and solid, with or
without comedonecrosis.
3 ICD-P invariably is associated with high-grade
and large-volume PCa seen in radical prosta-
tectomy.
for basal cells (Fig. 13E). In radical prostatec-
tomies, the IDC-P glands are intermingled with or
are in the immediate vicinity of high-grade (Glea-
son pattern 4/5) and high-volume PCa. Several
architectural patterns can be observed,40 includ-
ing the trabecular, in which cellular columns two
cells thick span the lumen and create elongated el-
liptic and crescent-shaped spaces between them
(Fig. 13A); the classic cribriform type, with thick
cell cords separated by uniform, punched-out
round spaces (Fig. 13B); and the solid pattern
with a solid mass of cells (Fig. 13C). Central com-
edonecrosis is present occasionally (Fig. 13D).
Cytologically, IDC-P frequently has two cell popu-
lations: peripheral cells that are tall, pleomorphic,
and mitotically active, and central cells with abun-
dant cytoplasm that are cuboidal, monomorphic,
and quiescent.
Differential Diagnosis
INTRADUCTAL CARCINOMA OF THE PROSTATE
 Central zone morphology
 Cribriform clear cell hyperplasia
 Cribriform high-grade PIN
 Cribriform PCa
 Urothelial carcinoma involving prostate ducts
and acini
 Metastatic carcinoma (eg, colorectal carci-
noma) to the prostate
Intraductal Carcinoma, Prostate:
Differential Diagnosis
Normal histologic variations, such as central zone
prostate glands, and benign glandular prolifera-
tion, such as cribriform clear cell hyperplasia,
can present as cribriform structures. Nuclear
atypia, mitosis, and comedonecrosis are absent,
however.
Cribriform high-grade PIN is rare. The glands are
small with round contour. The cells are relatively
uniform without marked nuclear pleomorphism or
necrosis. Unlike IDC-P, invasive cribriform cancer
lacks basal cell lining. Intraductal spread of uro-
thelial carcinoma, either from the bladder primary
or, exceedingly rarely, from the prostate primary,
may mimic IDC-P. Cytologically, urothelial carci-
noma typically is more pleomorphic than IDC-P.
A panel of immunostains often can resolve the di-
agnostic ambiguity. IDC-P stains positive for pros-
tate-specific markers, including PSA, PAP,
prostate-specific membrane antigen, and P501S,
whereas stains for basal cells, such as CK5/6,
34bE12, and P63, are positive only in the basal
cells at the periphery of the cancer glands. In con-
trast, urothelial carcinoma is negative for prostate-
specific markers and often is positive for the
markers that recognize the prostate basal cells.
Metastatic adenocarcinoma from other sites, colo-
rectal adenocarcinoma in particular, may have ex-
tensive necrosis and mimic IDC-P. Clinical history
and prudent use of immunostains (CDX-2 for colo-
rectal adenocarcinoma) can lead to a correct
diagnosis.
Intraductal Carcinoma, Prostate: Diagnosis
Cohen and colleagues40 proposed five major crite-
ria that are critical to the diagnosis of IDC-P and
several minor criteria that are helpful and support
this diagnosis. The major criteria that always are
present in IDC-P include (1) large-caliber glands
that are more than twice the size of normal periph-
eral zone gland structures and (2) are lined by
basal cells as identified with basal cell markers.
These glands are filled with cytologically malignant
cells (3) that always span the entire glandular lu-
men (4). The fifth major criterion, central comedo-
necrosis, although not always present, is
a common finding in IDC-P but is exceedingly
rare in high-grade PIN. Minor criteria include fre-
quent right-angle branching and rounded contours
in IDC-P glands in contrast to the undulating out-
lines of benign glands and high-grade PIN.
Guo and colleagues41 also proposed a set of
morphologic criteria in prostate biopsy that define
IDC-P as malignant epithelial cells filling large acini
and prostatic ducts with at least partial
 Prostatic Adenocarcinoma 65

Fig. 11. High-grade PIN.

(A) At low magnification,
high-grade PIN glands
(left) have architecture
similar to but appear
darker than the adjacent
normal glands (right). (B)
Secretory cells show
nuclear crowding and
stratification. Nuclei are
enlarged with coarse
and hyperchromatic chro-
matin and prominent
nucleoli.
66 Zhou & Magi-Galluzzi

Fig. 12. Architectural

patterns of high-grade
PIN. Secretory cells form
(A) undulating mounds
(tufted pattern) or (B)
cellular columns without
fibrovascular cores (mi-
cropapillary pattern).
 Prostatic Adenocarcinoma 67

Fig. 12. (C) The flat pat-

tern has no significant
architectural changes.
(D) The cribriform pat-
tern has complex archi-
tecture with Roman
bridges and cribriform
formations.
68 Zhou & Magi-Galluzzi

Fig. 13. Intraductal carci-

noma of the prostate.
Several architectural
patterns can be ob-
served, including (A) the
trabecular pattern, in
which two-cell-thick
cellular columns span
the lumen and create
elongated elliptic and
crescent-shaped spaces
between them; (B) the
classical cribriform type,
with thick cell cords
separated by uniform
punched-out round
spaces; and (C) the solid
pattern with a solid
mass of cells.
 Prostatic Adenocarcinoma 69

Fig. 13. (D) Central com-

edonecrosis occasionally
can be present.
70 Zhou & Magi-Galluzzi
preservation of basal cells forming either solid or
dense cribriform patterns or loose cribriform or mi-
cropapillary patterns with either marked nuclear
atypia (nuclear size six times normal or larger) or
comedonecrosis.
Pitfalls
INTRADUCTAL CARCINOMA OF THE PROSTATE
! IDC-P is difficult to diagnose and differentiate
from cribriform high-grade PIN on prostate
biopsy with limited material.
! Any atypical cribriform lesions with signifi-
cant cytologic atypia or comedonecrosis
should be regarded as IDC-P.
Fig. 13. (E) The basal cell
layers are present or
at least are partially
preserved and can be
confirmed by P63
immunostain.
Intraductal Carcinoma, Prostate: Prognosis
The importance of recognizing IDC-P lies in its as-
sociation with a poorer prognosis than otherwise
would be attributed to either high-grade PIN or
Gleason pattern 3 cancer (for review, see40).
IDC-P is associated with high-grade and high-vol-
ume cancer39,42,43,44 and has been found to have
prognostic significance independent of Gleason
grade, pathologic stage, and tumor volume.43,44
Therefore, the presence of IDC-P should be
sought and reported in radical prostatectomy.
IDC-P deserves special mention in reports of pros-
tate biopsy. If a high-grade (Gleason pattern 4 or 5)
invasive component is present with IDC-P, the
diagnosis of IDC-P seems to be of academic
interest. When associated with a Gleason pattern
3 component, however, IDC-P should be docu-
mented, and its poor prognostic significance
should be mentioned. One solution could be grad-
ing the IDC-P component as pattern 4 or 5. If
IDC-P is not associated with an invasive compo-
nent in prostate biopsy, however, it is more difficult
to distinguish from cribriform high-grade PIN, and it
is prudent to diagnose it as IDC-P with a comment
that IDC-P is often associated with high-grade
Table 1
Differential diagnosis of prostate carcinoma

Differential Diagnosis Architectural Features Cytologic Features Immunohistochemistry

Normal Seminal vesicle/ Central lumen with surrounding Scattered cells with prominent Basal cell markers positive
prostatic/ ejaculatory clusters of smaller glands degenerative nuclear atypia Secretory cell positive for PSA
non-prostatic ducts Nuclear pseudoinclusion and MUC 6
structures Golden brown pigments
Verumontanum Closely packed small acini beneath Prominent nucleoli negative Basal cells positive
mucosal gland urethral mucosa Lipofuscin pigment positive
hyperplasia Orange-brown dense luminal secretion Basal cells positive
Cowper’s glands Lobular collection of dimorphic Acini with voluminous, pale PAP negative
population of ducts and mucinous acini cytoplasm PSA negative or positive in
Intermixed with skeletal muscle fibers heterogeneous clumpy fashion
in a minority of cases
Paraganglia Most common in periprostatic tissue Clear or amphophilic, granular Neuroendocrine markers positive
Small nest of clear cells with cytoplasm PSA, PAP negative
prominent vascular pattern Inconspicuous nucleoli
Often associated with nerve
Mesonephric Lobular arrangement of small tubules Tubules lined with single layer PSA, PAP negative

Prostatic Adenocarcinoma
remnants with dense, eosinophilic intraluminal of cuboidal or flat epithelium HMWCK positive
secretion
Benign prostatic Partial Lobular configuration often maintained May have mild nuclear atypia Basal cells markers positive but often
lesions atrophy Pale glands with irregular or angulated patchy or even absent in some glands
contour AMACR weakly positive in some glands
Atrophy involving some glands or part
of a gland
Postatrophic Centrally dilated atrophic gland Atrophic cytoplasm Basal cell markers positive
hyperplasia surrounded by clustered smaller Inconspicuous nucleoli
atrophic glands
Stroma may be sclerotic
(continued on next page)

71
 72
Table 1
Differential diagnosis of prostate carcinoma

Zhou & Magi-Galluzzi

Differential Diagnosis Architectural Features Cytologic Features Immunohistochemistry
Urothelial Stratification of elongated cells Elongated nuclei with nuclear Basal cell markers positive
metaplasia underneath the secretory cells grooves
Cells perpendicular to basement Perinuclear clearing
membrane
Squamous Associated with inflammation, Intercellular bridge Basal cell markers positive
metaplasia infarction, or androgen ablation Abundant squamoid cytoplasm
therapy Immature form may have
Small, solid nests with admixed prominent nucleoli
inflammation
Basal cell Acinar, cribriform and solid growth Bland oval or elongated cells PSA, PAP negative
hyperplasia patterns Occasionally have prominent Basel cell markers positive
Squamous metaplasia, intraluminal nucleoli
calcifications, or intracytoplasmic
eosinophilic globules may be present
Adenosis Lobular collection of small and large Small and large glands exhibit Basal cells immunostain may be
glands that are intermixed together similar cytologic features patchy or absent in some
Prominent nucleoli absent small glands
Sclerosing Mixture of well-formed glands, Thickened basement membrane Basal cells positive for P63, HMWCK,
adenosis cords, or single cells and spindle cells around glands S-100, and actin
Nonspecific Mixed inflammatory process centered Containing lymphocytes, PSA, PAP and pan-cytokeratin
granulomatous around acini or duct histiocytes, neutrophils, negative, CD68 positive
prostatitis eosinophils, plasma cells
Multinucleated giant cells
rarely seen
Benign Nodular arrangement of small No cytologic atypia Basal cell markers positive
prostatic and large glands Basal cells positive
hypertrophy
High-grade PIN Architecture similar to, but glands Amphophilic cytoplasm Basal cell markers highlight basal cell
darker than, adjacent benign glands Nuclear enlargement with layers which may be discontinuous
prominent nucleoli, coarse or even absent in smaller glands
chromatin
Radiation Lobular configuration Scattered cells with marked Basal cell markers positive, AMACR
effect in Individual glands with marked degenerative nuclear atypia positive but may be reduced
benign irregular contour
glands Multilayered cells
 Other Urothelial Rounded, solid nests of pleomorphic
malignant carcinoma cells in an intensely inflamed
lesions background
Small cell Diffuse sheets of small blue cells
carcinoma May intermix with acinar PCa
component
Basal cell Infiltrating nests, cords, trabeculae,
carcinoma and sheets
Adenoid cystic carcinoma pattern
with extensive luminal formation
with cribriform architecture
Malignant features: infiltrative growth
pattern, extraprostatic extension,
perineural invasion, necrosis and
stromal desmoplasia
Squamous cell Squamous cell carcinoma occurs as pure
carcinoma squamous cell carcinoma of the prostate,
PCa with squamous component, urothelial
carcinoma of the prostate with squamous
differentiation, and urothelial carcinoma
of the urinary bladder with squamous cell
differentiation growing into the prostate
Abbreviation: HMWCK, high-molecular-weight cytokeratin.
Greater nuclear pleomorphism CK7, CK20, K903, and P63 positive
and mitotic activity Prostate-specific markers negative
Dense eosinophilic cytoplasm
More prominent squamous
differentiation
Tumor cells uniform with dense Positive for at least one neuroendocrine
round or oval nuclei, diffuse marker
chromatin, inconspicuous Prostate-specific markers and AMACR
nucleoli, and very scant positive in a minority of cases
cytoplasm TTF-1 positive in about 50% of the cases
Uniform cell with scant amount Bcl-2 diffusely positive
of cytoplasm Basal cell markers highlight multiple
layers of cells
Identical to squamous cell Squamous component of PCa may
carcinoma of other anatomic be weakly and focally positive for
sites and contains tumor cells prostate-specific markers
with abundant eosinophilic
and ‘‘glassy’’ cytoplasm
Prostatic Adenocarcinoma
73
74 Zhou & Magi-Galluzzi
invasive PCa. Therefore, immediate repeat biopsy
should be performed with the expectation that
a high-grade PCa will be detected.
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