Diagnosis of adenocarcinoma in prostate needle biopsy tissue
P A Humphrey
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J Clin Pathol 2007;60:35–42. doi: 10.1136/jcp.2005.036442
Prostate cancer is a major public health problem throughout the
developed world. For patients with clinically localised prostate
cancer, the diagnosis is typically established by
histopathological examination of prostate needle biopsy
samples. Major and minor criteria are used to establish the
diagnosis, based on the microscopic appearance of slides
stained using haematoxylin and eosin. Major criteria include an
infiltrative glandular growth pattern, an absence of basal cells
and nuclear atypia in the form of nucleomegaly and
nucleolomegaly. In difficult cases, basal cell absence may be
confirmed by immunohistochemical stains for high-molecular-
weight cytokeratins (marked with antibody 34bE12) or p63,
which are basal cell markers. Minor criteria include intraluminal
wispy blue mucin, pink amorphous secretions, mitotic figures,
intraluminal crystalloids, adjacent high-grade prostatic
intraepithelial neoplasia, amphophilic cytoplasm and nuclear
hyperchromasia. Another useful diagnostic marker detectable
by immunohistochemistry is a-methylacyl coenzyme A
racemase (AMACR), an enzyme selectively expressed in
neoplastic glandular epithelium. Cocktails of antibodies
directed against basal cell markers and AMACR are
particularly useful in evaluating small foci of atypical glands,
and in substantiating a diagnosis of a minimal
adenocarcinoma. Reporting of adenocarcinoma in needle
biopsy specimens should always include the Gleason grade and
measures of tumour extent in the needle core tissue. Measures
of tumour extent are (1) number of cores positive for cancer in
the number of cores examined, (2) percentage of needle core
tissue affected by carcinoma and (3) linear millimetres of
represents 19% of all cancers diagnosed in developed
Incidence rates are high in North America, northern
and western Europe, and Australia and New
of a definitive diagnosis of prostate cancer is the
histopathological interpretation of transrectal 18-
gauge needle core biopsy specimens, it is critical for
diagnostic pathologists to appreciate the histomor-
phological features of prostatic carcinoma in needle
biopsy tissue, and to have an organised approach to
the establishment of the diagnosis.
The histopathological diagnosis of adenocarci-
Dr P A Humphrey,
Department of Pathology
School of Medicine, PO Box
8118, 660 South Euclid
Avenue, St Louis, MO
63110, USA; humphrey@
Accepted 11 August 2006
cancer in the world and the second most common
cancer in men, with 679 000 new cases.1This
presents a unique set of challenges. Firstly, early
detection efforts, including screening with the
prostate-specific antigen (PSA) and digital rectal
examination, have resulted in identification of
lower-stage and smaller-volume carcinomas of the
prostate.2–5As a result, many PSA-detected carcino-
mas comprise ,5% of needle core tissue. Secondly, it
can be difficult to appreciate an infiltrative archi-
tectural pattern of growth in thin 18-gauge needle
core biopsy specimens. Finally, the needle cores can
fragment, which can also generate problems in
The focus of this review is an approach to the
histopathological diagnosis of carcinoma in pros-
tate needle biopsy specimens, especially limited or
minimal adenocarcinoma. We define minimal
carcinoma in needle biopsy tissue as a tumour
with size ,1 mm in the greatest dimension.6
Another definition of minimal adenocarcinoma is
cancer involving ,5% of needle core tissue.7The
first four sections include discussion on major and
minor criteria for the diagnosis of prostate
carcinoma on the basis of sections stained with
haematoxylin and eosin (H&E), features consid-
ered specific for carcinoma and minimal carci-
noma. Next, entities in the differential diagnosis of
prostatic adenocarcinoma are briefly presented,
followed by information on the use of ancillary
diagnostic studies, particularly the use of immu-
nohistochemical staining. The final section dis-
cusses the reporting of prostatic carcinoma in
prostate needle biopsy tissue.
MAJOR CRITERIA FOR DIAGNOSIS OF
ADENOCARCINOMA IN PROSTATE NEEDLE
BIOPSY TISSUE SECTIONS
Diagnosis of prostatic carcinoma requires a synth-
esis of a constellation of histological attributes that
allows for a definitive diagnosis. A conceptual
framework for a rationale approach to this
diagnosis entails application of major and minor
criteria (box 1).8 9
Before searching for these criteria, it is impor-
tant to scan sections of the needle core tissue, at
both low-power and high-power magnification, in
order to appreciate the architecture and cytological
features of benign glands (if present) in the tissue.
The arrangement of the benign glands and the
nuclear appearances of the lining cells (both basal
and luminal secretory) serve as important points
of reference for comparison when evaluating
atypical glands because there can be substantial
variability between individual cases in histological
Abbreviations: AMACR, a-methylacyl coenzyme A
racemase; H&E, haematoxylin and eosin; PIN, prostatic
intraepithelial neoplasia; PSA, prostate-specific antigen;
PSAP, prostatic acid phosphatase
characteristics because of differences in fixation, section
thickness and H&E staining.
The initial search using light microscopy should be an
assessment for the first of the major criteria, an infiltrative
growth pattern, which often presents as small malignant glands
extending between or around larger, more complex (and often
paler) benign glands (fig 1). These Gleason pattern 3
adenocarcinomas are currently the most common pattern
recognised in needle biopsy specimens.10–16They exhibit variably
sized individual and discrete glands.13 14In carcinomas that are
minimal (,1 mm)6or limited10in extent in needle biopsy
specimens, the presence of a few malignant acini between the
benign glands is indicative of invasion although the glands
appear only embedded within the stroma (fig 2). This deceptive
appearance is because the invading glands do not usually elicit
a desmoplastic or inflammatory response that characterises
many invasive carcinomas at other anatomical sites. A
distinctive pattern of infiltration is the formation of a column
of malignant glands spanning the width of the needle core
(fig 3). The infiltrative character of high-grade Gleason pattern
4 prostatic carcinoma in needle biopsy specimens is typified by
ragged invasion of fused microacinar (fig 4), cribriform or
papillary masses. Linkage of carcinoma cells into chains and
cords also indicates poorly differentiated Gleason pattern 4
adenocarcinoma.11 12 14Another descriptor of Gleason pattern 4
is ill-defined glands with poorly formed glandular lumina.13
High-grade carcinoma can also invade as sheets (fig 5), with
destruction and effacement of benign prostatic tissue, or be
manifested as comedocarcinoma (fig 6). These arrangements
represent Gleason pattern 5, which is uncommon in needle
biopsy specimens.12 15 16
In some cases, benign prostate glands are not present to serve
as landmarks to evaluate for invasion. This can happen as a
result of destructive growth of the tumour, due to invasion into
an area of pure fibromuscular stroma, and due to invasion into
extraprostatic tissues, such as periprostatic adipose tissue or
seminal vesicle tissue. Destructive growth can occur with any
Gleason grade carcinoma that is extensive. Malignant prostatic
glands in thick smooth-muscle bundles in a needle biopsy
specimen can represent invasion of inadvertantly sampled
extraprostatic bladder neck, but it is difficult to be certain in a
needle biopsy specimen that this represents extraprostatic
spread and not prostatic stroma. Also, benign or malignant
prostatic glands can be observed in skeletal muscle tissue at the
apex, where skeletal muscle of the urogenital diaphragm
interdigitates into the prostate gland. The detection of
infiltrating carcinoma into the skeletal muscle in a needle
biopsy specimen does not necessarily equate with extraprostatic
spread. As incidental findings, periprostatic tissue can be found
in as many as 77% of needle biopsy specimens,
vesicle or ejaculatory duct tissue can be seen in about 20% of
specimens.18Periprostatic adipose tissue is most often seen at
the tips of the needle cores, and the presence of carcinoma in
this fat can be a useful diagnostic finding (fig 7). However, this
is rarely an isolated finding and is generally associated with
extensive carcinoma in the rest of the needle biopsy tissue.
Prostatic carcinoma infiltration into the seminal vesicle or
ejaculatory duct tissue is an uncommon, incidental discovery
(fig 8), which tends to be more common in more extensive,
higher-grade carcinoma in needle biopsy tissue. Thus, in
prostatic needle biopsy, carcinoma of the prostate can present
a range of images of infiltration, with invasion into prostatic as
well as extraprostatic tissues.
An infiltrative pattern is not evident for carcinomas with a
partially nodular configuration. In rare cases, we may see well-
circumscribed small-gland proliferations, with smooth, pushing
edges. These would be, by definition, well-differentiated
adenocarcinomas, with Gleason score 3–4.11–13However, an
entire Gleason score 3–4 nodule is not captured by needle
biopsy and, also, well-differentiated Gleason score 3 and 4
nodules are characteristically found in the transition zone of
the prostate, whereas it is the peripheral zone that is typically
targeted for needle biopsy. Most apparently, well-differentiated
adenocarcinomas in needle biopsy tissue actually represent
intermediate-grade carcinomas at follow-up radical prostatect-
omy,6such that it has been recommended that carcinomas with
Gleason score 3–4 should be rarely, if ever, assigned to
adenocarcinoma in needle biopsy tissue.13
Absence of basal cells in the atypical glands is the second of
the major criteria. Basal cells may assume a range of
appearances,19 20and so careful study of basal cells in glands
that are clearly benign is a vital exercise before scrutinising
abnormal glands of concern to rule out their presence in
malignant glands. Thin, well-fixed sections with quality H&E
staining are crucial for the appreciation of a single cell-lining
layer in malignant glands. A historic challenge for the surgical
Box 1: Criteria for the diagnosis of prostatic
N Major criteria
– Architectural: infiltrative small glands or cribriform glands
too large or irregular to represent high-grade prostatic
intraepithelial neoplasia (PIN)
– Single cell layer (absence of basal cells)
– Nuclear atypia: nuclear and nucleolar enlargement
N Minor criteria
– Intraluminal wispy blue mucin (blue-tinged mucinous
– Pink amorphous secretions
– Mitotic figures
– Intraluminal crystalloids
– Adjacent high-grade PIN
– Amphophilic cytoplasm
– Nuclear hyperchromasia
3+3=score 6, with invasion between and around larger, more complex
Crowded small glands of adenocarcinoma, Gleason grade
pathologist has been the distinction of periglandular stromal
fibroblasts from basal cells. Another common difficulty is that
distorted, crushed or poorly preserved carcinoma cells in
minimal cancer foci can be mistaken for basal cells. In such
cases, application of a basal cell-specific immunohistochemical
stain for high-molecular-weight cytokeratin (fig 9B) or p63
(fig 9C) can be diagnostically advantageous (also described in
Ancillary Diagnostic Studies). However, these immunostains
are not a ‘‘malignant stain’’, and Totten et al8put basal cells in
their proper context when they noted the following based on
examination of H&E-stained sections:
This basal cell layer is not always present in benign small
glands, so that its absence is not an absolute criterion of
carcinoma. Conversely, however, we have not seen it in any
case in which the diagnosis was cancer.8
Basal cells may be completely absent in scattered benign and
especially atrophic glands,21 22and a fragmented basal cell layer
is characteristic of atypical adenomatous hyperplasia (adeno-
sis)23 24where, on average, 50% of glands lack a basal cell layer.
Additional but rare benign mimickers of prostatic carcinoma
that can lack basal cells include mesonephric hyperplasia25and
nephrogenic adenoma.26 27Loss of basal cells in a few glands of
partial atrophy or crowded benign glands is the most common
problem that leads to diagnostic difficulty.28To emphasise,
absence of basal cells is a central finding in an atypical small
acinar proliferation, but by itself, it is not fully diagnostic of
Nuclear atypia in the form of nuclear enlargement and
nucleolar enlargement is the third of the major criteria for
diagnosis of adenocarcinoma. Nuclear atypia in malignant
glands most often manifests itself as nuclear enlargement and
prominent nucleoli (fig 10). Failure to detect prominent
nucleoli in prostatic carcinoma nuclei is probably multifactorial;
large nucleoli might be present but undetectable owing to poor
preservation, poor fixation, overstaining or section thickness.
This last factor of overly thick sections is an extremely common
problem. In addition, lack of chromatin clearing might
contribute to the inability to detect nucleoli. Finally, some
prostate cancers do not harbour macronucleoli. Examples
include foamy gland carcinoma that can have shrunken
nuclei,30prostatic carcinoma with androgen deprivation treat-
ment effect31and some well-differentiated adenocarcinomas
(so-called nucleolus-poor adenocarcinomas).32The last two
examples are usually not seen in needle biopsy tissue. One
essential point is that when macronucleoli are absent, there
should be significant nucleomegaly with or without nuclear
hyperchromasia to definitively diagnose carcinoma.
MINOR DIAGNOSTIC CRITERIA
Minor diagnostic criteria (box 1) are found on an individual
basis in a smaller proportion of cases than those with major
diagnostic criteria, with the exception of intraluminal amor-
phous pink material. These minor or ‘‘soft’’ diagnostic
attributes are not specific for carcinoma but are useful for
prompting in-depth study of the glands harbouring these
changes, with a view towards assessment of the aforemen-
tioned major diagnostic criteria. With the possible exception of
high-grade prostatic intraepithelial neoplasia (PIN), none of the
listed minor criteria should, by itself, be considered a
sufficiently atypical finding to warrant rebiopsy. (A recent
recommendation is that men do not need routine repeat needle
biopsy within the first year after the diagnosis of high-grade
DIAGNOSTIC FEATURES CONSIDERED SPECIFIC FOR
After assessment for major and minor criteria, the pathologist
should look for diagnostic features that have been forwarded as
specific for malignancy,34including perineural invasion (fig 11),
growth. The lack of fibrogenic or inflammatory response is evident.
Haphazard distribution of small acini indicative of infiltrative
width of the needle core tissue, a sign of invasion.
Column-like growth of minimal adenocarcinoma across the
Fused acinar adenocarcinoma, Gleason grade 4+4=score 8.
Adenocarcinoma in prostate needle biopsy tissue37
collagenous micronodules (also known as mucinous fibropla-
sia; fig 12),35and glomeruloid intraglandular projections.36
These findings are present less often in prostate needle biopsy
specimens compared with whole glands with carcinoma.37They
are rare in minimal prostatic adenocarcinoma,34and this
obviously diminishes their diagnostic usefulness in this setting
where they are needed most. Perineural invasion by carcinoma
can be found in 11–37% of needle biopsy specimens with
carcinoma,37but in only 0–3% of tissue with minimal or limited
prostate cancer.6 7 10 34True perineural invasion, which is
characteristic of adenocarcinoma of the prostate, needs to be
distinguished from benign glands abutting the prostatic
peripheral nerve.38–40Collagenous micronodules are seen in 1–
5% of all needle biopsy cases with carcinoma,37and in as low as
0.1% of cases with minimal carcinoma.6 7 34Glomerations are
discovered in 3–15% of carcinomas on needle biopsy,37but are
extremely rare in minimal carcinoma in needle biopsy tissues;
we saw only one case with a suggestion of glomeruloid
intraluminal tufting.6In another series,34not a single case
had glomerulations as a key feature in diagnosing very limited
cancer. Another finding specific for carcinoma—lymphovascu-
lar space invasion—is vanishingly rare in prostate needle biopsy
One of the major diagnostic challenges confronting the
histopathologist in interpretation of a prostate needle biopsy
specimen is the establishment of a malignant diagnosis based
on a minimal or limited amount of carcinoma in the needle
biopsy tissue. The major and minor diagnostic criteria should be
put into use here, just as for more extensive carcinoma. The
presence of a few small malignant glands located between
larger, more complex, paler benign glands is the most common
pattern of invasion in minimal carcinoma (fig 13), accounting
for 80% of cases in one series.10The second most common
pattern of infiltration of limited carcinoma was a haphazard
growth in stroma, without adjacent benign glands. Uncommon
patterns of growth that typically accompanied the common
patterns were cords of cells, single cells and cribriform glands.10
No definite quantitative threshold exists for the number of
glands required to establish a diagnosis of malignancy,
although most authorities require at least 2–3 glands (I prefer
three glands). Clearly though, each case must be interpreted on
it own merits such that a very few glands may be definitely
diagnostic in one case but not in another. Many cases of
minimal carcinoma harbour well over 2–3 glands. In our series,6
80% of minimal carcinoma foci contained .10 glands, and in a
second series,10the median number of malignant glands was
20. In a third series, the mean (standard deviation (SD))
number of acini to diagnose carcinoma was 17 (14).7In our
experience, the smallest number of atypical glands that formed
the basis for a definitive diagnosis of malignancy was 3–4. In
these cases, there should be excellent preservation of cellular
detail, without tangential sectioning, such that it was clear on
the H&E sections that basal cells were absent and that
considerable nuclear atypia (with numerous macronucleoli)
was present. Both of these major criteria are of immense
importance for these most minimal of the minimal carcinomas,
where discerning architectural abnormalities is difficult to
impossible. In another series on minimal (limited) carcinoma,
the lowest number of diagnostic glands was two.10At a
consensus conference,9most urological pathologists thought
that three glands constituted the typical lowest numerical cut-
off. Finally, in this era, there is a trend to confirm the diagnosis
of minimal adenocarcinoma with immunohistochemical stains
for basal cells and a-methylacyl coenzyme A racemase
(AMACR)29(described later in Ancillary Diagnostic Studies).
Sheet of prostatic adenocarcinoma, Gleason grade 5+5=score
Comedocarcinoma, high-grade Gleason pattern 5, with
periprostatic adipose tissue sampled by needle biopsy.
Extraprostatic extension by prostatic carcinoma into
DIFFERENTIAL DIAGNOSIS OF ADENOCARCINOMA
IN NEEDLE BIOPSY TISSUE
Numerous entities, both benign and malignant, should be
considered in the differential diagnosis of prostatic adenocarci-
noma.37In-depth discussion of these entities is beyond the
scope of this review.
Recent reviews have highlighted the benign lesions or
pseudoneoplasms (box 2) that may mimic prostatic adenocar-
cinoma.41 42Atypical adenomatous hyperplasia (adenosis) and
atrophy are the benign conditions that are most likely to be
misdiagnosed as prostatic carcinoma.28 41 42Crowded benign
glands may also be mistaken for prostatic adenocarcinoma.28
The pathologist should always consider the possibility of a
benign mimicker of prostatic carcinoma, particularly atrophy,
but also all other entities (box 2), before making a diagnosis of
adenocarcinoma of the prostate.
A descriptive diagnosis which may be rendered if the
histological or immunohistochemical findings are thought to
be worrisome but not fully diagnostic of carcinoma, is
atypia,33 43also known as atypical suspicious for carcinoma or
atypical small acinar proliferation. Such a diagnosis is given in
about 4–5% of all prostate needle biopsy specimens.33 43
The main non-prostatic, secondary malignancy to think
about before diagnosing prostatic carcinoma in needle biopsy
of the prostate is urothelial (transitional cell) carcinoma
involving the prostate.37 44
ANCILLARY DIAGNOSTIC STUDIES
The most valuable adjunctive study for the diagnosis of
adenocarcinoma of the prostate, particularly minimal adeno-
carcinoma, is immunohistochemistry with antibodies directed
against basal cells (34bE12 and p63) and AMACR (also known
as P504S or racemase). In the past, basal cell immunostains
were used by themselves. Currently, many laboratories combine
use of basal cell markers with an immunostain for AMACR,
sometimes in a cocktail.
Historically, the most widely used immunostain is mono-
clonal antibody 34bE12 (fig 9B), which binds to high-
molecular-weight cytokeratin proteins expressed in the cyto-
plasm of basal cells and not in luminal cells.21 29This antibody,
which also has been identified by its commercial catalogue
number CK903, is useful for documenting the absence of basal
cells in focal atypical small acinar proliferations, yet there are
caveats in the use and interpretation of this immunohisto-
chemical staining reaction. Firstly, absence of basal cells is an
important criterion for the histological diagnosis of prostatic
carcinoma, but is only one of several of the major criteria. Thus,
this immunostain, as other adjunctive studies, should be
interpreted in the context of all histological findings in the
particular case. Also, not all benign glands have basal cells.
Finally, this immunohistochemical stain is based on a negative
result to give a positive diagnosis of malignant neoplasm. Many
factors can cause failure of immunohistochemical staining, and
absence of proof is not proof of absence. So, it is absolutely
critical to study the immunostained cores for a positive internal
control—benign glands with a strong, positive basal cell signal.
seminal vesicle or ejaculatory duct wall. It is difficult to tell, on needle
biopsy, whether this is definitely a seminal vesicle or an ejaculatory duct.
Seminal vesicle or ejaculatory duct glands are crowded larger glands at
Penetration of small-gland prostatic adenocarcinoma into the
highlight the invasion of the malignant glands, which lack basal cells (brown signal).
Minimal adenocarcinoma. Compared with staining by haematoxylin and eosin (A), the 34bE12 (B) and p63 (C) immunohistochemical stains
some with prominent nucleoli, 4006.
Nuclear atypia in adenocarcinoma: appearance of nuclei,
Adenocarcinoma in prostate needle biopsy tissue39
Preferably, these benign glands are located near the adjacent
carcinoma (fig 9B) or are at least in the same core.
The 34bE12 immunostain can be useful as a confirmatory
measure in specific circumstances. It should not be used as a
screening test in all prostate needle biopsy specimens but rather
should be applied specifically in selected cases with selection and
the differential diagnosis driven by the histological appearance of
the H&E-stained slides. In the past 10 years, the use of basal cell
immunostains has increased: in a large series from 1995, only
2.8% of all prostate needle biopsy specimens were immunos-
tained with the antibody 34bE12,45compared with a recent series
from 2004, where immunostains were used in 22% of prostate
needle biopsy specimens.46Basal cell stains are most often
ordered in selected cases in which the differential diagnosis
encompassed atypical adenomatous hyperplasia (adenosis), PIN,
basalcellhyperplasiaandatrophy.45Theimmunostain also can be
used to distinguish cribriform high-grade PIN from cribriform
invasive carcinoma.47In one series of needle biopsy specimens, it
was concluded that the 34bE12 immunostain substantially
reduced the percentage of prostate needle biopsy cases diagnosed
One setting where basal cell markers, including the 34bE12
immunostain, can be particularly valuable is in biopsies after
radiation therapy for prostatic carcinoma, when the differential
diagnostic consideration based on H&E slides is radiation-
induced atypia in benign glands versus minimal residual
carcinoma.49 50In this setting, reactive basal cells can mimic
cancer cells cytologically in nuclear changes and, here, the
34bE12 immunostain can provide important diagnostic infor-
mation. Also, minimal residual carcinoma after hormonal
therapy can pose diagnostic challenges, and positive immunos-
tains for PSA and pan-cytokeratin, with a negative 34bE12
immunostain, can sometimes be helpful.50
Additional basal cell markers for the diagnosis of adenocar-
cinoma include p63 (fig 9C),51 52cytokeratins (CK) 5/6,53
cystatin A54and calcyclin.55The p63 immunostain, which
detects p63 protein in the nucleus of basal cells, seems to be
more sensitive in basal cell detection than the immunostain
using the 34bE12 antibody.29 56Some have combined p63 and
34bE12 antibodies in a cocktail.46 56 57Although in one study
this cocktail increased the sensitivity of basal cell detection and
reduced the staining variability,57data from a second study on
atypical glandular proliferations showed that there was little, if
any, advantage in using the cocktail compared with a p63
It would be desirable to diagnose adenocarcinoma and to have
a positive marker that is relatively specific for malignant prostatic
epithelial cells, in addition to the negative basal cell markers.
From immunohistochemical studies,29 58–69one such marker,
AMACR, is selective and very sensitive for carcinoma. About
80–100% of prostatic adenocarcinomas stain with AMACR. As
many as 21% of benign prostatic glands also stain, including
atrophy,29 67but the staining signal is usually more focal and
weaker than withcarcinoma.A misleadingresult can beobtained
withpartialatrophy, whereupto79%ofcases havebeenreported
to be AMACR positive.28This finding, combined with focal basal
lossand nuclear atypia70that may be seen in atrophy, could result
in a misdiagnosis of partial atrophy as adenocarcinoma. Most
high-grade PIN foci stain,64a minority of atypical adenomatous
hyperplasia casesstain,58andnephrogenicadenoma, whichrarely
involves the prostate, can also be positive.26 27This immunostain
can be quite helpful, as a confirmatory tool, in cases of minimal
carcinoma.61 62It may have utility in diagnosing carcinoma in
patients after radiotherapy and after hormonal therapy, although
its value here is less certain.29 49It is best interpreted only in a
histological context and in conjunction with 34bE12 or p63
Cocktails comprised of AMACR and a basal cell marker such
as p63,65–68or AMACR/p63/34bE12,69with single or two
chromogens, are useful for simultaneous assessment of these
markers in the same glands (fig 14). Application of such a
Perineural invasion, with focal intraneural invasion, by
adenocarcinoma in the prostate.
Collagenous micronodules, a feature thought to be specific for
Minimal adenocarcinoma, Gleason grade 3+3=score of 6.
cocktail is decidedly advantageous if only a small atypical focus
is present, and especially if the focus is present only on a single
section or slide that is available for immunohistochemical
evaluation.67Such cocktails can also be used on destained H&E-
stained sections, if unstained sections are unavailable.68
In certain cases, additional immunohistochemical studies are
indicated.29For example, in the differential diagnosis of focal
granulomatous prostatitis versus focal poorly differentiated
prostatic adenocarcinoma, a panel of antibodies to cytokeratins
(AE1/AE3), PSA, prostatic acid phosphatase (PSAP), lysozyme,
antimacrophage M and leucocyte common antigen (CD45)
reliably distinguished the disorders.71The differential diagnostic
investigation of prostatic carcinoma versus urothelial (transi-
tional cell) carcinoma in prostate needle biopsy tissue likewise
can be aided by using a targeted panel of antibodies,29including
PSA, PSAP, 34bE12 and thrombomodulin. PSA and PSAP are the
best prostatic markers in general, but they are not absolutely
specific and can stain benign and malignant non-prostatic cells
and tissue. Although usually resolved by examination of H&E-
stained slides, the distinction of small seminal vesicle glands and
minimal prostatic adenocarcinoma also can be accomplished by
PSA, PSAP and 34bE12 immunohistochemical studies, in which
seminal vesicle glands should be negative for the first two
immunostains and positive for the last one.
Genetic abnormalities such RNA overexpression or under-
expression, DNA ploidy, chromosomal anomalies, gain or loss
of specific DNA sequences, DNA methylation and specific gene
mutations are not used in the diagnosis of carcinoma in
prostate needle biopsy specimens.
The most clinically important attributes of adenocarcinoma in
prostate needle biopsy specimens that merit reporting are
Gleason grade and amount of tumour in the needle biopsy
tissue.11–13 72 73Measures of tumour extent in the needle biopsy
tissue include (1) number of positive needle cores in the total
number of cores, (2) percentage of positive cores, (3)
percentage of needle core tissue affected by carcinoma as
determined by visual inspection and (4) linear millimetres of
tumour extent. All these measures provide nearly equivalent
information, such that there is not a standard method of
appraising the tumour extent in a needle biopsy specimen.
Indeed, several measures should be given for the same set of
needle biopsies.72–74It is also worthwhile to report, for needle
core biopsies, perineural invasion by carcinoma, the presence of
extraprostatic carcinoma in adipose tissue or seminal vesicle,
and lymphvascular space invasion by carcinoma.73
Competing interests: None declared.
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biopsy specimens: diagnostic features and radical prostatectomy follow-up. Mod
immunohistochemical stain: p63 is detected in the nuclei of basal cells in benign glands (below), compared with granular cytoplasmic AMACR stain, with
apical luminal accentuation (above) in glands of adenocarcinoma, which lack p63. (B) 34bE12/p63/AMACR cocktail: 34bE12 and p63 antibody binding
to basal cells is indicated by brown stain, whereas red stain corresponds to AMACR detection. AMACR-positive, basal-cell-negative adenocarcinoma is on
the right, whereas benign, AMACR-negative, basal-cell-positive glands are on the left.
Basal cell markers/a-methylacyl-–coenzyme A racemase (AMACR) cocktails with one (A) and two (B) chromogens. (A) p63/AMACR cocktail
Box 2: Differential diagnosis of prostatic
adenocarcinoma: pseudoneoplasms of the
N Atypical adenomatous hyperplasia (adenosis)
N Crowded benign glands
N Basal cell hyperplasia
N Sclerosing adenosis
N Cribriform hyperplasia
N Mesonephric hyperplasia
N Nephrogenic metaplasia (adenoma)
N Verumontanum mucosal gland hyperplasia
N Squamous metaplasia
N Transitional cell metaplasia
N Radiation atypia
N Postoperative spindle cell nodule
N Atypical stromal cells
N Extramedullary haematopoiesis
N Cowper glands
N Paraganglia in prostate
N Benign glands adjacent to nerves and skeletal muscle
Adenocarcinoma in prostate needle biopsy tissue41
7 Iczkowski KA, Bostwick DG. Criteria for biopsy diagnosis of minimal volume
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atypical small acinar proliferation. Arch Pathol Lab Med 2000;124:98–107.
8 Totten RS, Heinemann MW, Hudson PB, et al. Microscopic differential diagnosis
of latent carcinoma of prostate. Arch Pathol 1953;55:131–41.
9 Algaba F, Epstein JI, Aldape HC, et al. Assessment of prostate carcinoma in core
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