1008 Prostate Needle Biopsy Interpretation: Updates and Problematic Areas

1008 Prostate Needle Biopsy Interpretation: Updates and Problematic
Omar Hameed, MD FASCP
Vanderbilt University Medical Center, Nashville, TN
Peter AHumphrey, Peter A MD FASCP
Washington University School of Medicine, St. Louis, MO
Wednesday, September 18, 2013, 10:00 AM - 11:50 AM
This course is designed to provide both pathologists in practice and those in training with an
effective and practical approach to the evaluation of prostate needle biopsy material. The focus
will be on (a) underdiagnosis of prostate cancer, specifically those deceptively-benign-appearing
carcinomas; (b) the latest modified approach to Gleason grading of carcinoma with its clinical
impact on patient management, including active surveillance and active therapy; (c) histologic
mimics of prostatic carcinoma; and (d) the utility and caveats of immunohistochemistry in the
evaluation of prostate needle biopsy material, specifically in the distinction between carcinoma
and its mimics. A large number of diagnostic images will be presented to convey the spectrum of
minimal and unusual variants of prostatic carcinoma, different Gleason grades, and
pseudoneoplastic lesions. A significant emphasis will placed on how to distinguish the latter
lesions from carcinoma and the role of immunohistochemistry in this regard.
Learning Objectives
1. Recognize (1) the most common deceptively benign-appearing prostatic carcinomas and
(2) the histologic mimickers of carcinoma, and understand the criteria utilized for their
diagnostic recognition.
2. Become proficient in application of the modified Gleason grading system, and to know
how Gleason grade and amount of cancer in prostate needle core tissue impact
management of patients with prostate cancer.
3. Recognize the utility and limitations of immunohistochemistry in the evaluation of
prostate needle biopsies and how it can (or cannot) be used to discriminate between
prostatic carcinoma and its mimics.
Speaker Disclosure
In the past 12 months, neither of us have had a significant financial interest or other relationship
with the manufacturer(s) of any products or providers of the services that will be discussed in
our presentation.
Peter A Humphrey, MD, PhD
Department of Pathology and Immunology
Washington University School of Medicine
Saint Louis, Missouri
[email protected]
Prostate cancer is a major public health problem throughout the developed world. For patients
with clinically-localized prostate cancer, the diagnosis is typically established by
histopathological examination of prostate needle biopsy samples. Major and minor criteria are
utilized to establish the diagnosis, based upon the microscopic appearance of hematoxylin and
eosin-stained slides. 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 34betaE12) and/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 alpha-methylacyl CoA racemase (AMACR), an enzyme
selectively expressed in neoplastic glandular epithelium. Cocktails of antibodies directed against
basal cell markers and AMACR are particularly useful in evaluation of small foci of atypical
glands, and are useful in substantiating a diagnosis of a minimal adenocarcinoma. Reporting of
adenocarcinoma in needle biopsy should always include the Gleason grade and measures of
tumor extent in the needle core tissue. Measures of tumor extent are number of cores positive for
cancer out of number of cores examined, percentage of needle core tissue involved by
carcinoma, and linear millimeters of carcinoma present.
Prostate cancer is the fifth most common cancer in the world and the second most common
cancer in men, with 679,000 new cases.1 This represents 19% of all cancers diagnosed in
developed countries and 5.3 % in developing countries.1 Incidence rates are high in North
America, Northern and Western Europe, and Australia and New Zealand.1 In 2013 in the United
States there is an estimated 239,000 new cases, representing 28% of all new cancers diagnosed in
men. Since a primary approach for establishment of a definitive diagnosis of prostate cancer is
histopathologic interpretation of transrectal 18-gauge needle core biopsy specimens, it is critical
for diagnostic pathologists to appreciate the histomorphological features of prostatic carcinoma
in needle biopsy tissue, and to have an organized approach to the establishment of the diagnosis.
The histopathological diagnosis of adenocarcinoma of the prostate in needle core biopsy presents
a unique set of challenges. First, early detection efforts, including screening with prostate
specific antigen (PSA) and digital rectal examination, also have resulted in identification of
lower stage and smaller volume carcinomas of the prostate.2-5 As a result, many PSA-detected
carcinomas comprise less than 5% of needle core tissue. Secondly, it can be difficult to
appreciate an infiltrative architectural pattern of growth in thin 18-gauge needle core biopsies.
Lastly, the needle cores can fragment which can also generate problems in interpretation.
The focus of this review is an approach to histopathological diagnosis of carcinoma in prostate
needle biopsy specimens, especially limited or minimal adenocarcinoma. We define minimal
carcinoma in needle biopsy tissue as tumor less than 1 mm in greatest dimension.6 Another
definition of minimal adenocarcinoma is cancer involving less than 5% of needle core tissue.7 In
the first four sections there is discussion on major and minor criteria for the diagnosis of prostate
carcinoma based on H&E-stained sections, features considered specific for carcinoma, and
minimal carcinoma. Next, entities in the differential diagnosis of prostatic adenocarcinoma are
briefly presented. The following segment includes information on use of ancillary diagnostic
studies, particularly the use of immunohistochemical staining. Finally, the reporting of prostatic
carcinoma in prostate needle biopsy tissue is addressed.
Diagnosis of prostatic carcinoma requires a synthesis 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 (Table 1).8,9
The first assessment one should perform in hematoxylin and eosin-stained needle biopsy
sections, from fixed (usually formalin-fixed) tissue from paraffin blocks, is a search for the first
of the major criteria, an infiltrative growth pattern, which frequently presents as the presence of
small malignant glands extending between and/or around larger, more complex, (and often paler)
benign glands. These Gleason pattern 3 adenocarcinomas are currently the most common pattern
recognized in needle biopsy.10-12 They exhibit variably-sized individual and discrete glands.13,14
In carcinomas that are minimal (less than 1 mm)6 or limited10 in extent in needle biopsy, the
presence of a few malignant acini between the benign glands is indicative of invasion even
though the glands appear only embedded within the stroma. This deceptive appearance is due to
the facts that the invading glands do not usually elicit a desmoplastic or inflammatory response,
that characterizes many invasive carcinomas at the anatomic sites. A distinctive pattern of
infiltration is a formation of a column of malignant glands spanning the width of the needle core.
The infiltrative character of high-grade (Gleason patterns 4 or 5 and score 7-10) prostatic
carcinoma in needle biopsy is typified by ragged invasion of fused microacinar, cribriform or
papillary masses. Linkage of carcinoma cells into chains and cords also indicates poorly-
differentiated Gleason pattern 4 adenocarcinoma.11,12,14 Another descriptor of Gleason pattern 4
is ill-defined glands with poorly formed glandular lumina.13 High-grade carcinoma can also
invade as sheets, with destruction and effacement of benign prostatic tissue, or be manifested as
comedocarcinoma. These arrangements represent Gleason pattern 5, which is uncommon in
needle biopsy.12,15,16
In some cases, benign prostate glands are not present to serve as landmarks to evaluate for
invasion. This can happen due to destructive growth of tumor, 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. Malignant prostatic glands in thick smooth muscle
bundles in needle biopsy can represent invasion of inadvertantly-sampled extraprostatic bladder
neck, but it is difficult to be certain in needle biopsy 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 skeletal muscle in needle biopsy
does not necessarily equate with extraprostatic spread. As incidental findings, periprostatic
tissue can be found in up to 77% of needle biopsies17 and seminal vesicle or ejaculatory duct
tissue can be seen in up to 20% of needle biopsies.18 Periprostatic 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 . 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
seminal vesicle/ejaculatory duct tissue is an uncommon, incidental discovery, which tends to be
more common in more extensive, higher-grade carcinoma in needle biopsy. 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.
In a minority of needle biopsy cases, an infiltrative pattern is not evident. These appear to be
well-differentiated, Gleason score 3 to 4, adenocarcinomas that are, by definition, wellcircumscribed small gland proliferations, with smooth, pushing edges.11-13 However, an entire
Gleason score 3 to 4 nodule is usually 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 prostatectomy,6 such that it has been recommended that
Gleason score 3 to 4 should be rarely, if ever, assigned to adenocarcinoma in needle biopsy
The second of the major criteria for diagnosis of adenocarcinoma is absence of basal cells in the
atypical glands. Basal cells may assume a range of appearances, 19,20 making careful study of
basal cells in glands that are clearly benign a vital exercise 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 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 mimic basal cells. In cases such as these, application of a basal cell-specific
immunohistochemical stain for high-molecular-weight cytokeratin and/or p63 can be
diagnostically advantageous. (See the section on ancillary studies). However, these
immunostains are not a “malignant stain,” and Totten and colleagues8 put basal cells in their
proper context when they noted the following, based on scrutiny 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,21,22 and
a fragmented basal cell layer is characteristic of atypical adenomatous hyperplasia (adenosis),23,24
where, 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 hyperplasia25 and
nephrogenic adenoma.26,27 Loss of basal cells in a few glands of partial atrophy or crowded
benign glands is a most common problem that leads to diagnostic difficulty.28 To emphasize,
absence of basal cells is a central finding in an atypical small acinar proliferation, but by itself, it
is not fully diagnostic of adenocarcinoma.29
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. Failure to detect prominent
nucleoli in prostatic carcinoma nuclei is likely multifactorial; large nucleoli might be present but
undetectable owing to poor preservation, poor fixation, overstaining, or section thickeness. This
last factor of overly thick sections is an extremely common problem. In addition, lack of
chromatin clearing might contribute to inability to detect nucleoli. Lastly, some prostate cancers
do not harbor macronucleoli. Examples include foamy gland carcinoma, which can have
shrunken nuclei,30 prostatic carcinoma with androgen deprivation therapy effect,31 and some
well-differentiated adenocarcinomas (so-called nucleolus-poor adenocarcinomas).32 The latter
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 (Table 1) are found, on an individual basis, in a lower proportion of
cases compared with major diagnostic criteria, with the exception of intraluminal amorphous
pink material. These minor or “soft” diagnostic attributes are not specific for carcinoma but are
useful for prompting in-depth study of the glands harboring these changes, with a view toward
assessment of the aforementioned major diagnostic criteria. With the possible exception of highgrade prostatic intraepithelial neoplasia (PIN), none of the listed minor criteria should, by
themselves, be considered a sufficiently atypical finding to warrant rebiopsy. (Note that a recent
recommendation is that men do not need routine repeat needle biopsy within the first year
following a diagnosis of high-grade PIN.33)
Diagnostic features that have been forwarded as specific for malignancy34 – perineural invasion,
collagenous micronodules (also known as mucinous fibroplasia),35 and glomeruloid
intraglandular projections36 – are present less often in prostate needle biopsy compared to whole
glands with carcinoma.37 These findings are rare in minimal prostatic adenocarcinoma,34 and
this obviously diminishes their diagnostic usefulness in this setting where they are needed most.
Perineural invasion was identified in 0% to 3% of minimal or limited prostate cancer
cases,6,7,10,34 and collagenous micronodules were seen in 0.1% to 5% of cases.6,7,34 We saw only
1 case with a suggestion of glomeruloid intraluminal tufting.6 In another series,34 not a single
case had glomerulations as a key feature in diagnosing very limited cancer. True perineural
invasion, which is characteristic of adenocarcinoma of the prostate, needs to be distinguished
from benign glands abutting prostatic peripheral nerve.38-40 Collagenous micronodules are a
distinctive, but uncommon, type of stromal response to invasive prostatic carcinoma, which often
exhibits mucinous differentiation.35 Adenocarcinomas of the prostate with glomeruloid features
are remarkable for intraglandular tufts of malignant cells that resemble (somewhat) renal
glomeruli in their low-power appearance.36 Another finding specific for carcinoma –
lymphvascular space invasion – is vanishingly rare in prostate needle biopsy tissue.
One of the major diagnostic challenges confronting the histopathologist in prostate needle
biopsy interpretation is the definite in establishment of a malignant diagnosis based on a minimal
or limited amount of carcinoma in needle biopsy. 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, accounting for fully 80% of cases in one
series.10 The 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
The major criteria do not include a quantitative threshold for the number of glands
required to establish a diagnosis of malignancy. In our series,6 80% of minimal carcinoma foci
contained more than 10 glands and in a second series,10 the median number of malignant glands
was 20. In a third series the mean +/- SD number of acini to diagnose carcinoma was 17 +/- 14.7
It is possible to diagnose invasive carcinoma based on just a few glands. In our experience, the
smallest number of atypical glands which formed the basis for a definitive diagnosis of
malignancy was three to four. 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 significant nuclear atypia was present. Both of these major criteria are of
immense importance for these most minimal of the minimal carcinomas, where architectural
abnormalities are difficult to impossible to discern. In another series on minimal (limited)
carcinoma, the lowest number of diagnostic glands was two.10 At a consensus conference,9 most
urologic pathologists felt 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 AMACR (see below section on ancillary
Numerous entities, both benign and malignant, should be considered in the differential diagnosis
of prostatic adenocarcinoma. In-depth discussion of these entities is beyond the scope of this
review. Recent reviews have highlighted the benign lesions, or pseudoneoplasms, that may
mimic prostatic adenocarcinoma.41-43 It is important to note that atypical adenomatous
hyperplasia (adenosis) and atrophy are the benign conditions that are most likely to be
misdiagnosed as prostatic carcinoma.29,41-43 Crowded benign glands may also be mistaken for
prostatic adenocarcinoma.29
A descriptive diagnosis that may be rendered if the histological and/or immunohistochemical
findings are felt to be worrisome, but not fully diagnostic of carcinoma is atypia,33,44 also known
as atypical suspicious for carcinoma or atypical small acinar proliferation (ASAP). Such a
diagnosis is given in about 4 to 5% of all prostate needle biopsy cases.33,44
Focal glandular atypia, also known as atypical small acinar proliferation (ASAP), is a descriptive
diagnosis for a gland or group of glands with architectural or cytological atypia that does not
allow for a definitive diagnosis of reactive atypia, adenosis, PIN, or carcinoma. Distortion
artifact, section thickness, and overstaining can contribute to difficulty in interpretation.
Immunostains can be very useful in addressing the differential diagnosis of atypia vs. minimal
adenocarcinoma (see below). Patients with a diagnosis of atypia (ASAP) should be clinically
followed and re-biopsied because about 43% of men are diagnosed with carcinoma on rebiopsy.72
The most valuable adjunctive study for the diagnosis of adenocarcinoma of the prostate,
particularly minimal adenocarcinoma, is immunohistochemistry with antibodies directed against
basal cells (34betaE12 and p63) and alpha-methylacyl CoA racemase (AMACR; also known as
Historically, the most widely used immunostain employed monoclonal antibody 34betaE12,
which binds to high-molecular-weight cytokeratins expressed in the cytoplasm of basal cells and
not in luminal cells.21,29 This antibody, which also has been identified by its commercial catalog
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
immunohistochemical staining reaction. First, basal cell absence is an important criterion for the
histologic diagnosis of prostatic carcinoma but is only one of several of the major criteria. That
is, this immunostain, like other adjunctive studies, should be interpreted in the context of all
histologic findings in the case. Also, as noted above, 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.
Preferably, these benign glands are located near the adjacent carcinoma or are at least in the
same core.
With these pitfalls in mind, the 34betaE12 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 histologic appearance of the H&E-stained slides. In the last
10 years, the use of basal cell immunostains has increased : In a large series form 1995, only
2.8% of all prostate needle biopsy specimens were immunostained with antibody 34betaE12,45
compared to a recent series from 2004, where immunostains were used in 22% of prostate needle
biopsy cases.46 In our recent prospective experience spanning a full year, we ordered
immunostains on 11% of all prostate needle core biopsy cases. Basal cell stains are most often
ordered to evaluate a focus of atypical glands. They have also been ordered in selected cases in
which the differential diagnosis encompassed atypical adenomatous hyperplasia (adenosis), PIN,
basal cell hyperplasia, and atrophy.45
The immunostain also can be used to distinguish
cribriform high-grade PIN from cribriform invasive carcinoma.47 In one series of needle biopsy
specimens, it was concluded that the 34betaE12 immunostain substantially reduced the
percentage of prostate needle biopsy cases diagnosed as atypical.48
The 34betaE12 immunostain can be particularly valuable when the differential diagnostic
consideration is radiation-induced atypia vs focal minimal residual carcinoma in patients with
prostate cancer treated by radiation therapy.49,50 In this setting, reactive basal cells can mimic
cancer cells cytologically in nuclear alterations, and, here, the 34betaE12 immunostain can
provide important diagnostic information. Minimal residual carcinoma after hormonal therapy
also can pose diagnostic challenges, and positive immunostains for PSA and pan-cytokeratin,
with a negative 34betaE12 immunostain, sometimes can be helpful.50
Additional basal cell markers for the diagnosis of adenocarcinoma include p63,51,52 cytokeratins
(CK) 5/6,53 cystatin A,54 and calcyclin.55 The p63 immunostain appears be more sensitive in
basal cell detection than the immunostain using the 34betaE12 antibody.29,56 Some have
combined p63 and 34betaE12 antibodies in a cocktail.46,56,57 While this cocktail increased the
sensitivity of basal cell detection and reduced the staining variability,57 in one study of atypical
glandular proliferations there was little, if any advantage in using the cocktail compared to a p63
immunostain alone.56 While basal cell antibody or antibodies may still be used alone in
immunohistochemistry, a trend is for their inclusion in a cocktail with an AMACR antibody.
It would be desirable in diagnosing adenocarcinoma to have a positive marker that is relatively
specific for malignant prostatic epithelial cells, in addition to the negative basal cell markers.
One such marker, alpha-methylacyl-CoA racemase (AMACR), is selective and very sensitive for
carcinoma, based upon immunohistochemical studies.29,58-69 About 80-100% of prostatic
adenocarcinomas stain. Up to 21% of benign prostatic glands also stain, including atrophy,reviwed
in 29,67
but the staining signal is usually more focal and weaker compared to carcinoma. A
misleading result can be obtained with partial atrophy, where up to 79% of cases have reported
to be AMACR-positive.28 This finding, combined with focal basal loss and nuclear atypia70 that
may be seen in atrophy could result in a misdiagnosis of partial atrophy as adenocarcinoma.
Most high-grade PIN foci stain,64 a minority of atypical adenomatous hyperplasia cases stain,58
and nephrogenic adenoma, which rarely involves the prostate, can also be positive.26,27 This
immunostain can be quite helpful, as a confirmatory tool, in cases of minimal carcinoma.61,62 It
is best interpreted only in histologic context and in conjunction with 34betaE12 and/or p63
Cocktails comprised of AMACR and a basal cell marker such as p6365-68 or
AMACR/p63/34betaE12,69 with single or two chromogens, are useful for simultaneous
assessment of these markers in the same glands. Application of such a cocktail is diagnostically
advantageous if only a small atypical focus on a single section or slide is available for
immunohistochemical evaluation.67 Such cocktails can also be used on destained H and Estained sections, if unstained sections are unavailable.68
Immunohistochemistry for ERG has also been studied as a prostate cancer marker.70a-70d ERG
protein is an ETS transcription factor, with expression in the nuclei of normal endothelial cells,
vascular neoplasms, and the subset of prostate cancers that harbor ERG gene fusions
(predominantly TMPRSS2-ERG fusions). ERG expression is seen in about one-half of prostate
carcinomas and can also be seen in high-grade PIN. It is uncommonly expressed in benign
prostatic glands. Diagnostically, ERG immunohistochemistry could potentially be used in
difficult cases where the AMACR/basal cell cocktail immunostains are not contributory. Added
value beyond the AMACR/basal cell cocktail immunostains has not been proven for ERG
immunostaining. In one study ERG immunostains did not aid in the workup of atypical glands
that were suspicious for carcinoma.70d AMACR was superior to ERG in diagnosis of foamy
gland carcinoma,70e which can be difficult diagnosis based on examination of H and E-stained
sections alone.
Finally, in certain cases, additional immunohistochemical studies are indicated.29 For example, in
the differential diagnosis of focal granulomatous prostatitis vs focal poorly differentiated
prostatic adenocarcinoma, a panel of antibodies to cytokeratins (AE1/AE3), PSA, prostatic acid
phosphatase (PSAP), lysozyme, antimacrophage M, and leukocyte common antigen (CD45)
reliably distinguished the disorders.71 The differential diagnostic workup of prostatic carcinoma
vs urothelial (transitional cell) carcinoma in prostate needle biopsy tissue likewise can be aided
by use of a targeted panel of antibodies,29 including PSA, PSAP, 34betaE12, GATA3, and
thrombomodulin. PSA and PSAP are the best prostatic markers in general, but they are not
absolutely specific and can stain benign and malignant nonprostatic cells and tissue. PSAnegative carcinomas comprise 3 to 13% of high-grade prostatic carcinomas. In these cases,
P501S (prostein), PSMA, and NKX3.1 immunostains may be helpful in establishing prostatic
origin.29a 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, AMACR, and 34betaE12 or p63 immunohistochemical studies, in which seminal
vesicle glands should be negative for the first three immunostains and positive for the last two.
Genetic abnormalities such RNA overexpression or underexpression, 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.
Deceptively-benign appearing adenocarcinoma of the prostate may assume the form of
atrophic pattern adenocarcinoma,72-74 pseudohyperplastic pattern adenocarcinoma,75-77 and foamy
gland adenocarcinoma.78-81 These pseudobenign carcinomas figure prominently in needle biopsy
series on false-negative diagnoses of prostate cancer.82,83 A recently described variant of both
pseudohyperplastic and atrophic patterns is the microcystic pattern.84
The most important attributes of adenocarcinoma in prostate needle biopsy that merit
reporting are Gleason grade and amount of tumor in needle biopsy tissue.11-13,85,86, 88-90 Measures
of tumor extent in needle biopsy include number of positive needle cores out of total number of
cores, percentage of positive cores, percentage of needle core tissue involved by carcinoma as
determined by visual inspection, and linear millimeters of tumor extent. It is likely that all these
measures provide nearly equivalent information, such that there is not a standard method of
appraising needle biopsy tumor extent. Indeed, several measures should be given for the same
set of needle biopsies.85-87 It 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.86,88,89
Table 1
Criteria for the Diagnosis of Prostatic Adenocarcinoma*
Major Criteria
Architectural: infiltrative small glands or cribriform glands too large or irregular to represent
high-grade PIN
Single cell layer (absence of basal cells)
Nuclear atypia: nuclear and nucleolar enlargement
Minor Criteria
Intraluminal wispy blue mucin (blue-tinged mucinous secretions)
Pink amorphous secretions
Mitotic figures
Intraluminal crystalloids
Adjacent high-grade PIN
Amphophilic cytoplasm
Nuclear hyperchromasia
PIN, prostatic intraepithelial neoplasia
* Adapted from Algaba et al9
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Peter A. Humphrey, MD, PhD
Department of Pathology and Immunology,
Washington University School of Medicine
Saint Louis, Missouri
[email protected]
Grade may be defined as a degree of severity in illness (1). Histological grade of a
neoplastic process is often equated with the degree of differentiation of the neoplastic cells. In
the last three quarters of the twentieth century, over forty histologic grading systems for prostatic
carcinoma have been proposed. These systems have typically utilized differentiation capacity,
architectural growth patterns, mitotic activity, and nuclear abnormalities in generation of a
histological grade assignment. In Europe a three-tiered grading system was widely used (2a).
Currently, the most widely used grading scheme in the United States and worldwide is
the Gleason system (2-10), while other grading methods are applied in some laboratories. The
Gleason grading system is recommended for use by the 2004 World Health Organization “blue
book” and the 2010 AJCC/UICC cancer staging manual. The International Society of Urological
Pathology (ISUP) published recommendations on a modified scheme that was based on new data
and recognition of new histological variants of prostatic adenocarcinoma. Newly encountered
areas of difficulty and controversial areas where no data or consensus exist were also addressed
(8a). The most recent modification of the Gleason grading system is presented in the 2011 AFIP
Fascicle (2). It is this modified scheme that should be used (Figure 1).
There are particular challenges in the application of Gleason grading scheme to thin
needle biopsy tissue samples. The aims of this review are to provide a general approach to using
the Gleason system, to discuss grading issues relevant particularly to needle core biopsy tissues,
to present new findings on grading in needle core tissue, and to explore possible avenues for
future improvement and investigation.
General Approach
The Gleason grading system was developed by Dr. Donald F. Gleason, a pathologist in
Minnesota, and members of the Veterans Administration Cooperative Urological Research
Group (VACURG) (3-8). From 1960 to 1975 the VACURG enrolled roughly 5,000 prostate
cancer patients in prospective randomized clinical trials. One of the outstanding strengths of the
Gleason grading system is that it was tested in this large patient population, with long-term
follow-up that included use of survival as an endpoint.
The Gleason grading system is based entirely on the histologic pattern of arrangement of
carcinoma cells in H&E-stained prostatic tissue sections. Specifically, the method is one of
categorization of histologic patterns at relatively low magnification, using a 4X or 10X lens, by
the extent of glandular differentiation and the pattern of growth of the tumor in the prostatic
stroma (8). Use of a 20X lens is allowable to confirm a low-power impression, such as
identification of gland fusion or necrosis (8a). Nine growth patterns were consolidated into five
grades and these were illustrated in a drawing by Dr. Gleason. (Illustrations of the drawing and
photomicrographs of these patterns may be found in references 10).
The five basic grade patterns are used to generate a histologic score, which can range
from 2-10, by adding the primary grade pattern and the secondary grade pattern. The primary
pattern is the one that is predominant in area, by simple visual inspection. The secondary pattern
is the second most common pattern. If only one grade is in the tissue sample, that grade is
multiplied by two to give the score. What should one do if there are two patterns and one pattern
is less than 5% of all the tumor? According to the Gleason approach of 1990, if the second grade
is less than 3% of the total tumor, it is ignored, and the primary grade is again doubled to give
the Gleason score (8). However, this has been modified in the recent consensus meeting (8a) : In
the setting of high-grade carcinoma (patterns 4 or 5), one should ignore lower-grade patterns if
they occupy less than 5% of the area of the tumor. So if there is 98% pattern 4 and 2% pattern 3,
the score should be 4 + 4 = 8. For focal high-grade carcinoma in needle biopsy, though, one
should always incorporate the high-grade pattern. So, for 98% pattern 3 and 2% pattern 4, the
score is 3 + 4 = 7. For radical prostatectomy with less than 5% pattern 4 or 5, this should be
noted in a comment (8a).
Gleason sum, Gleason grade, combined Gleason grade, and category score have been
used as synonyms for Gleason score, but “histological pattern score” was the initial 1974
designation for the sum of the two patterns (4) and “histologic score” has endured in usage in the
writings of Gleason (5-8).
The assignment of a Gleason score, which is the addition of the two most common
patterns, essentially averages the primary and secondary grades. This procedure appears to be
unique in grading of human cancers, where, for other malignancies, it is the worst grade that
determines patient outcome. Peculiarly, for prostatic carcinoma, when there are two different
Gleason grade patterns, the cancer death rates are intermediate between the rates for patients
with only the pure form of each of those two grades (6-8).
The Gleason grading system allows for two separate grade patterns in an individual tissue
sample, but the histomorphological appearance of prostatic carcinoma is more heterogeneous
than this. Indeed, in one study (11), an average of 2.7 Gleason grade patterns (range 1-5) was
found in carcinomas in whole prostate glands. Three additional papers report that 14-23% of
patients had more than two grades in sections of their prostatic carcinoma (13,14, 14a). In one of
these reports (13), 3% of cases had 4 different Gleason patterns. The number of grades assigned
depends on tumor sample size and size of the tumor in the whole gland. So, more than two
grades is more often observed in TURP chips (28% of cases) compared to needle biopsies (4-7%
of cases) (12,14), and tumors greater than 1-2 cm3 in size tended to have more than 2 grades
There are data on prostatic carcinomas with more than 2 grades. Gleason wrote that the
VACURG was unable to acquire enough three-grade tumors to evaluate their behavior (8), and
proposed an algorithm to provide a Gleason score in cases with more than two grades (8).
Recent data on radical prostatectomy specimens indicate that a high-grade Gleason pattern 4 or 5
that is a tertiary component occupying less than 5% of the tumor influences pathological stage
and progression rates (14a,15,16, 16a). In one investigation using needle biopsies, patients with
Gleason score 7 and tertiary pattern 5 were more likely to suffer from bone metastasis compared
to patients without such a tertiary 5 pattern (18). In a second study on Gleason score 7 in needle
core tissue, men with tertiary Gleason pattern 5 had a significantly shorter time to PSA failure
after therapy (surgery or radiation therapy with or without hormonal therapy) (18a). Currently,
the recommendation for needle biopsy is that for cases with patterns 3,4, and 5, that the primary
pattern and the highest grade should be recorded (8a); in this case the score would be 3+5=8.
For radical prostatectomy cases, one should assign the Gleason score based on the primary and
secondary patterns with a comment on the tertiary pattern (8a).
Application of Modified Gleason Grading
In general, use of the modified Gleason scoring rather than conventional Gleason scoring
has resulted in upgrading (18b,18c). For example, use of the modified as opposed to the
conventional Gleason grading scheme for needle core biopsies resulted in this change in
Gleason score distribution : Gleason scores 2-4 decreased from 2.7% to 0%, score 5 decreased
from 12.2% to 0.3%, score 6 decreased from 48.4% to 22%, and score 7 increased from 25.5% to
67.9% (18c). In one study, the modified Gleason score in needle biopsy predicted biochemical
failure after surgery, whereas the conventional Gleason score in needle biopsy did not (18d). In
another series the modified Gleason grading in needle biopsies identified a higher number of
patients in the aggressive Gleason score 8-10 group who had a worse outcome after radical
prostatectomy (18e).
Gleason Grade of Histological Variants of Prostatic Carcinoma
The Gleason system is designed for application to all untreated prostatic glandular
carcinomas. Recommendations for grading variants have been made (8a, 10, 19). Additional
recent recommendations include assignment of Gleason pattern 4 to glomeruloid
adenocarcinoma (19a), Gleason pattern 4 to all cribriform adenocarcinomas (19b), and pattern 3
to PIN-like adenocarcionomas (19c, 19d). Squamous cell and urothelial carcinomas of the
prostate should not be graded by the Gleason method.
Grading in Fine Needle Aspirates
Attempts have been made to apply Gleason grading to fine needle aspiration biopsy
samples of prostatic carcinoma, but since epithelial-stromal relationships are not preserved in
these specimens, this is not advisable. Rather, traditional cytologic grading as well, moderately,
or poorly-differentiated, is recommended (20).
Grading in Different Prostatic Tissue Samples
Gleason grading should be performed in all prostatic tissue samples, including needle
core biopsy specimens. Indeed, of Gleason’s original series of 2,911 patients, 60% were graded
solely on the basis of a needle biopsy (6).
Gleason Grading in Needle Biopsy Samples
A Gleason grade should be given for all adenocarcinomas in prostate needle biopsy
tissue, including all variants and focal or minimal (limited) adenocarcinoma. The only times a
Gleason grade should not assigned to adenocarcinoma in prostate needle biopsy is if there is
hormonal or radiation treatment effect (see below).
A Gleason grade should be assigned to needle biopsy cases with minimal prostatic
carcinoma, defined as less than 1 mm of tumor (21,22). Of importance, a small amount of
carcinoma in needle biopsy tissue should not be equated with well-differentiated Gleason score 2
to 4 adenocarcinoma. Most minimal adenocarcinomas in needle biopsy tissue are intermediate
Gleason grade, usually of a score of 6.
Comparisons of Gleason grade in needle biopsy with Gleason grade in the matched
whole prostate gland indicate exact correlation in 43% of cases (range 20-88%) and agreement to
within ± 1 score unit in 77% of 3,789 cases (range 62-97%) (reviewed in 2,18b). Undergrading
of tumor in the needle biopsy, with a higher Gleason score in the matched whole gland, is the
most common problem, occurring, on average, in 42% of all cases. Overgrading of carcinoma in
needle biopsy tissue also takes place, but with a much lower mean of 15% of all cases.
Gleason score 2 to 4 should rarely, if ever, be assigned to adenocarcinoma in needle core
tissue from the prostate (8a,22a). This is so because the peripheral zone is typically targeted by
the prostate needle biopsy procedure and Gleason score 2-4 adenocarcinomas are not typically
found in this location. Also, it is not feasible for a needle core to capture an entire Gleason score
2-4 nodule and so even if the tumor appears partially circumscribed in needle core tissue, it is not
possible to determine if the entire carcinoma focus is completely circumscribed, which is
necessary to diagnose Gleason grade 2-4 adenocarcinoma (8a).
As noted above, reporting of adenocarcinoma with high-grade tertiary Gleason grade is
different for needle biopsy vs. radical prostatectomy tissues. To reiterate, for needle biopsy
tissue it is critical to incorporate any tertiary high-grade Gleason pattern 4 or 5 into the final
score, regardless of the amount of high-grade pattern 4 or 5.
For needle biopsy cases there are several sources of grading error, including difficulty in
appreciation of an infiltrative growth pattern, tissue sampling error (related to the small amount
of tissue supplied by needle biopsy and grade heterogeneity), tissue distortion, pathologist
experience, and observer variability.
Gleason Grading in Larger Tissue Samples
Assignment of Gleason grade to larger tissue samples, including TURP chips, and open
(simple) and radical prostatectomy specimens is often more straightforward than in needle
biopsy cases. A distinctive characteristic of carcinoma grade in TURP chips and open (simple)
enucleation prostatectomy specimens is that well-differentiated Gleason score 2 to 4
adenocarcinomas are much more common in these tissue specimens compared to needle biopsies
and radical prostatectomy specimens. Cautery artifact can generate difficulty in grading
carcinoma in TURP chips. The Gleason grade of incidental stage T1a/b carcinoma tends to be
somewhat less than the grade in the whole gland since the TURP procedure samples the
transition zone where lower-grade carcinomas arise.
The Gleason grading system, like all histological grading methods, possesses an inherent
degree of subjectivity. Intraobserver and interobserver variability does exist (18a,23,24). Recent
data suggest that for needle biopsy grading, pathologist training and experience (25) can
influence the degree of interobserver agreement. For pathologists, improvement in Gleason
grading of carcinoma can be achieved by participation in educational courses at meetings and by
use of tutorial programs (25,26) including web-site programs [at
www.pathology.jhu.edu/prostate (25) and http://www.pathology.ks.se/egevad/gleason.html (26)].
Grading in Metastatic Deposits
Gleason grading of prostatic carcinoma outside the prostate and in metastatic deposits has
been reported, but the Gleason system was not originally designed for this purpose as it is based
upon epithelial (carcinoma)-stromal architectural relationships within the prostate.
Grading after Radiation and Hormonal Therapy
In general, the Gleason grading system should be applied only to tumor that shows no
evidence of treatment effect. For radiation therapy cases, where there is no evidence or minimal
evidence of therapy effect, Gleason grading may be utilized. Hormonal therapy can cause
pattern alterations resembling high Gleason grades. Overall, the consensus view is that one
should not report histologic grade after hormonal therapy (27).
Relationship of Gleason Grade to Pathologic and Clinical Endpoints
Increasing Gleason grade is directly related to a number of histopathological endpoints
and clinical endpoints (for a review, see reference 2). Indeed, Gleason grade is one of the most
powerful prognostic indicators for patients with prostate cancer.
Needle Biopsy Gleason Grade and Prediction of Pathologic Stage, Insignificant Cancer, and
Response to Treatment
Needle biopsy Gleason grade is in routine clinical use in the “Partin Tables” is pretreatment prediction of pathologic stage (27a). Gleason grade may also be used in nomograms to
predict low-volume and low-grade organ-confined prostate cancers that are likely to be clinically
indolent or insignificant (27b,27c); patients with these cancers could be candidates for expectant
management. Indeed, needle biopsy Gleason grade is always one of the criteria (usually along
with clinical stage, PSA level, and amount of tumor in needle core tissue) in selecting patients
for active surveillance (27d).
Needle biopsy Gleason grade is one of the key factors used in models and nomograms to
predict response to therapy, including surgery (radical prostatectomy) (27e) and radiation therapy
Experimental Approaches
Grade, as a measure of intrinsic biological aggressiveness, may be assessed in the future
by both structural (morphological and morphometric) and functional means. One proposed
morphological approach is quantitation of amount of high-grade (percentage Gleason pattern 4 or
5) carcinoma (28-30). Overall, use of the % 4/5 parameter in needle biopsy seems to be limited
by a high false-negative rate (31). The amount of carcinoma comprised of high-grade Gleason
grade pattern 4 or 5 has potential for adding information to standard Gleason grade assignment in
TURP and radical prostatectomy tissues, while its utility in needle core tissue is currently
Quantitative measures of nuclear abnormalities have also been forwarded as grading
tools. Genotypic grading of DNA abnormalities might one day be used in conjunction with the
current phenotypic grading. Functional gene expression profiles of prostatic carcinoma might
one day provide information on carcinoma aggressiveness, or grade, but this is currently an
experimental tool (31a). In one study, gene expression profiling of carcinoma in radical
prostatectomy tissues provided only slight information about prostate cancer recurrence once
clinical and pathological parameters, including Gleason grade were known (32). In another
study, a 157-gene signature helped predict lethal prostate cancer amongst men with Gleason
score 7 disease (32a).
Reporting of Gleason Grade for Needle Core Biopsies
To summarize, Gleason grade should be provided for all carcinomas in needle biopsy
tissue (8a,17,33) even for minute, minimal, or limited carcinomas. In needle biopsy tissue, if
there is one Gleason pattern, it should be doubled to yield a score. High-grade pattern 4 or 5
should be incorporated into the score, even if it represents a minor secondary or tertiary pattern.
So, for 96% pattern 3 and 4% pattern 4, the score is 3 + 4 = 7. If a lower grade represents less
than 5% of tumor, it should not be incorporated into the score. So if there is 97% pattern 4 and
3% pattern 3, the score should be 4 + 4 = 8. For cases with three patterns, the primary pattern
and the highest grade should be recorded (8a). For a needle biopsy case with 3+4+5, the score
would be 3+5=8. For needle biopsy cores, Gleason grade should be assigned to carcinoma in
each separate core or as a composite for the biopsy cores in each separately-submitted container,
designated by site. Two studies have presented data that each core should be given a separate
grade (34,35). Difficulty may arise if more than one core is submitted per container and the
cores fragment into pieces. Still, it is important to know that clinically the core with highest
score will be used for clinical management purposes.
Reporting of Gleason Grade in Larger Tissue Samples
Gleason grade reporting in TURP chips and enucleation specimens should follow the
standard Gleason method of reporting the predominant pattern as the primary grade and the
second most common pattern as the secondary grade. If a tertiary Gleason pattern 4 or 5 is
detected, it should definitely be noted. Radical prostatectomy Gleason grade should be assigned
in standard fashion, with the most common and the secondary Gleason patterns in the whole
gland used to determine the primary and secondary Gleason grades. There are published
recommendations to grade only the “dominant nodule” or to report separate grades for separate
tumors in the whole gland (17), but many prostate glands lack a dominant nodule and no data
exist to support reporting of separate tumors. A tertiary high-grade component, when present,
should definitely be reported since this has an impact on prognosis (15,16). The
recommendation that is evidence-based (15,16) is to keep the original Gleason score (based on
the first most common and second most common patterns), with a notation on the presence of a
tertiary high-grade component.
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Figure 1. AFIP Modified Gleason Grading Scheme
Omar Hameed, MD
Department of Pathology, Microbiology and Immunology, Department of Urologic Surgery, and
the Vanderbilt Ingram Cancer Center, Vanderbilt University and Vanderbilt University Medical
Center, Nashville, TN
1211 Medical Center Drive, 3020D VUH
Nashville, TN 37232-7415
E-mail: [email protected]
The differential diagnoses of prostatic carcinoma include a number of histological
mimics that should be known to avoid misdiagnosis. Pseudoneoplastic lesions in the prostate
include those of prostatic epithelial origin, the commonest being atrophy, adenosis (atypical
adenomatous hyperplasia), basal cell hyperplasia, and crowded benign glands, as well as those of
non-prostatic origin such as seminal vesicle epithelium. Such lesions often mimic lower-grade
prostatic adenocarcinoma, while others, such as clear cell cribriform hyperplasia and
granulomatous prostatitis for example, are in the differential diagnosis of Gleason grade 4 or 5
adenocarcinoma. Diagnostic awareness of the salient histomorphological and relevant
immunohistochemical features of these prostatic pseudoneoplasms is critical to avoid rendering
false positive diagnoses of malignancy.
There are many normal structures and pathological lesions in the genitourinary system
that can histologically resemble neoplastic processes. Although some, such as nephrogenic
adenoma, can be seen in different locations, most are identified in particular organs and, as such,
have unique differential diagnostic considerations specific to that organ. This review will focus
on those pseudoneoplastic conditions that are in the differential diagnosis of prostatic
There are many lesions that can mimic prostatic adenocarcinoma histologically. Such
lesions can be broadly divided into those that mimic lower grade adenocarcinomas (Gleason
grade 3 or less), and those that mimic higher grade tumors. A more detailed and practically
useful classification that we 1 and others 2 have used in classifying these lesions is based on the
architectural pattern(s) seen in routine hematoxylin and eosin (H&E)-stained sections (Table 1).
The benign entities most often misdiagnosed as prostatic adenocarcinoma are atrophy,
crowded benign glands, adenosis (atypical adenomatous hyperplasia), and basal cell hyperplasia,
depending on the study and type of tissue sample (needle biopsy vs. TURP). In one review of
535 consecutive needle biopsies, seven (1.3%) were classified as false-positives.3 These seven
cases were comprised of 5 cases of adenosis (atypical adenomatous hyperplasia) and 2 cases of
atrophy. A second investigation on needle core biopsy tissue found partial atrophy and crowded
benign glands to be the most frequent benign mimickers of prostatic carcinoma.4 In a study that
focused on TURP chips, cases misinterpreted as adenocarcinoma included atypical adenomatous
hyperplasia (26% of the false-positive cases), basal cell hyperplasia (26%), atrophy (16%),
sclerosing adenosis (10%), high-grade prostatic intraepithelial neoplasia (10%),
xanthogranulomatous prostatitis (6%), florid cribriform hyperplasia (3%), and post-atrophic
hyperplasia (3%).5
TABLE 1: Histological mimickers of prostatic adenocarcinoma
Small gland pattern
Lesions of prostatic epithelial origin
Adenosis (atypical adenomatous hyperplasia)
Crowded benign glands
Sclerosing adenosis
Basal cell hyperplasia
Radiation and reactive atypia
Verumontanum mucosal gland hyperplasia
Lesions of non-prostatic epithelial origin
Seminal vesicle and ejaculatory duct epithelium
Cowper’s glands
Mesonephric remnants
Colonic glands
Nephrogenic adenoma
Large and cribriform gland patterns
(Clear cell) cribriform hyperplasia
Cribriform basal cell hyperplasia
Medium to large-sized hyperplastic glands
Solid and non-glandular patterns
Granulomatous prostatitis
Prostatic xanthoma
Signet ring-like change
Small gland pattern; lesions of prostatic epithelial origin
Atrophy is a common age-related process that represents one of the benign lesions most
frequently misdiagnosed as carcinoma. Atrophy may be classified as simple atrophy, simple
atrophy with cyst formation, and postatrophic hyperplasia.6 Sclerotic atrophy has also been a
recognized category.7 These patterns are often admixed. Proliferative atrophy and proliferative
inflammatory atrophy are optional designations.6 The hallmark of atrophy is cytoplasmic volume
loss, while most prostatic adenocarcinomas harbor a moderate amount of cytoplasm. Most cases
of simple atrophy of the prostate can readily be distinguished from prostatic adenocarcinoma on
account of their dark basophilic silhouette on H&E sections secondary to their crowded
hyperchromatic and bland-appearing nuclei with high nuclear/cytoplasmic ratios, in the face of
gland space formation by the atrophic glands. Furthermore, the glands may assume a lobular or
circumscribed arrangement without infiltration around and between larger, clearly benign glands.
Basal cells may be difficult to recognize in atrophic glands due to nuclear compression and
crowding. Additionally, it is sometimes difficult to identify basal cells even with the use of
immunohistochemistry (IHC) as up to 23% of atrophic glands can be completely negative for
basal cell markers.4, 8 A disrupted basal cell layer can also be seen, with a reduced number of
basal cells in individual glands.
Compared to simple atrophy, partial atrophy and postatrophic hyperplasia are usually
more difficult to distinguish from prostatic adenocarcinoma. Partial atrophy usually appears as
collection of crowded small pale glands, sometimes with a stellate shape, composed of clear cells
and usually with bland nuclei and inconspicuous nucleoli.9-11 The nuclei in partial atrophy glands
can assume an elongated cylindrical shape and visible nucleoli can be seen in up to one quarter
of cases.9 Partial atrophy can resemble prostatic adenocarcinomas composed of clear cells such
as some low grade and transition zone carcinomas 12 as well as foamy gland carcinoma.13 In
postatrophic hyperplasia the small regular acini are closely packed and a central duct may be
seen. The constituent cells may harbor prominent nucleoli, particularly when acute inflammation
is present,14 further contributing to the difficulty in separating it from adenocarcinoma.
The stroma in atrophy is altered by a pale fibrosis with periacinar collagen deposition,
which can impart a sclerotic appearance. This alteration is present is all forms of atrophy except
partial atrophy. This sclerosis should not be confused with a desmoplastic response to invasive
prostatic carcinoma, which is unusual. Inflammation is common in atrophy and infrequent in
adenocarcinoma. Other minor diagnostic criteria include luminal contents: Corpora amylacea
are more likely to be detected in atrophic glands compared to adenocarcinoma, whereas
crystalloids and wispy blue mucin are conversely more prevalent in adenocarcinoma than benign
Atrophy, especially partial atrophy, may also be mistaken for prostatic adenocarcinoma
due to its frequent (at least focal) expression of α-methylacyl coenzyme-A racemase (AMACR).
1, 4, 10, 15
This, along with the fact that basal cells are often difficult to discern in this form of
atrophy as well, may also account, at least in part, to why it represented the most frequent lesion
sent in for consultation in a recent study.4 The presence of elongated nuclei that are
perpendicular to the gland circumference, irregular nuclear placement, identification of basal
cells (by H&E or IHC), and/or merging into adjacent simple atrophy, when present, can all help
point to the correct diagnosis of partial atrophy. Lastly, one should be cognizant that atrophic
pattern adenocarcinoma does exist.16-18 Features favoring benign atrophy over atrophic pattern
adenocarcinoma include lack of infiltrative pattern of atrophic glands between larger benign
glands, lack of co-existing usual acinar adenocarcinoma with a moderate amount of cytoplasm,
and lack of diffuse, significant cytological atypia in the glands of concern.
Adenosis (Atypical adenomatous hyperplasia)
Adenosis, or atypical adenomatous hyperplasia (AAH) is another common mimicker of
prostatic adenocarcinoma on both needle biopsy and transurethral resection specimens.19-21 It is
invariably an incidental histologic finding usually localized in the transition zone, and is thereby
seen more often in TURP chips. The incidence in needle biopsy is less than 1%. Histologically,
it is characterized by a nodular proliferation of closely packed small glands that often merge with
larger, more complex glands. While the periphery is typically rounded, in a minority of cases the
small acini can extend into surrounding stroma in a pseudoinfiltrative pattern. Uncommonly, the
small acini exhibit a more extensive, crowded, and nonlobular distribution, in a pattern termed
diffuse adenosis of the peripheral zone.22 23
By definition, the basal cell layer in adenosis is fragmented, with some small acini
completely lacking basal cells. Immunohistochemical staining with antibody 34betaE12
demonstrates absence of basal cells in about one-half of all glands (with a range of 10% to
90%).9,11 Cytologically, the luminal cells have cytoplasm that is pale, and cleared to granular,
and round to oval nuclei usually with inconspicuous nucleoli. Intraluminal wispy blue mucin
and/or crystalloids are sometimes present and up 18% of cases have been found to express
AMACR,24 all features that may lead to diagnostic confusion with adenocarcinoma. A very
useful fact to remember in this situation is that basal cells are at least focally evident (by H&E
and/or IHC) in all cases of adenosis, and that the nuclear atypia in adenosis is not as marked as in
Crowded benign glands
Foci of crowded small benign prostatic glands, less than what would be considered
diagnostic of adenosis,may also simulate adenocarcinoma and have also been found to be
common benign lesion for which a second opinion is requested.4 Although a lobular pattern of
growth may not be easily identified in needle biopsy samples, an infiltrative pattern of growth
and cytological atypia are lacking, and basal cells can almost always be identified (at least
focally) by routine H&E sections or IHC.
Sclerosing adenosis
This lesion, rarely seen in needle biopsy specimens,25 is characterized by a circumscribed
proliferation of small glandular structures separated by a cellular and myxoid spindle cell stroma.
25, 26
The glands of sclerosing adenosis are surrounded by a thick eosinophilic membranous
structure in most cases. There is true myoepithelial differentiation, with the spindled cells being
immunoreactive for muscle specific actin and S100 protein. Basal cells are also present. The
spindled stroma, identification of basal and myoepithelial cells, and lack of appreciable nuclear
atypia are useful in distinguishing sclerosing adenosis from adenocarcinoma.
Basal cell hyperplasia (BCH)
Basal cell hyperplasia is classically seen in the transition zone, but can also occur in the
peripheral zone 27 and may cause diagnostic confusion with high-grade prostatic intraepithelial
neoplasia or adenocarcinoma in TURP chips and needle core tissue. Basal cell hyperplasia is
characterized by two or more layers of basal cells with a range of growth patterns, including
acinar, cribriform/pseudocribriform, and solid patterns, 23, 28-30 or mixtures of these patterns.
These growths are often focal, but in the transition zone they can form nodules and also can
involve nodules of benign prostatic hyperplasia. An infiltrative appearance due to presence of
the hyperplastic foci between benign glands may be seen. There can be focal, eccentric, partial
gland involvement to a symmetrical circumferential proliferation with central retention of
secretory cell layer. Complete luminal space loss with the creation of solid small nests may also
be noted in basal cell hyperplasia. The cribriform (adenoid basal cell) pattern is rare.23, 29
Additional unusual morphologic patterns include basal cell hyperplasia with
intracytoplasmic eosinophilic globules and squamous features.29 The stroma surrounding basal
cell hyperplasia may be similar to adjacent uninvolved prostate, may reveal a few concentric
layers of cellular or mxyoid compressed stroma, or may show a hypercellular, hyperplastic
stroma, which has been called sclerosing basal cell hyperplasia. Microcalcifications are seen in
nests in about one half of cases.28 The basal cells themselves are basophilic or slate grey with
scant cytoplasm and round to oval nuclei.
The differential diagnosis for basal cell hyperplasia centers mainly on high-grade
prostatic intraepithelial neoplasia (HGPIN), particularly when nucleoli are present, but basal cell
hyperplasia is a uniform cell population and does not exhibit the tufted and micropapillary
patterns commonly present in PIN. Tubular and cribriform basal cell hyperplasia can be
mistaken for adenocarcinoma but again the multilayered uniform basaloid cell population is the
key finding that aids in diagnostic recognition. The finding of small solid basaloid nests is a
diagnostic clue pointing towards basal cell hyperplasia since such nesting is not typical of
adenocarcinoma unless the carcinoma is high-grade and extensive. The aforementioned stromal
alterations favor basal cell hyperplasia over adenocarcinoma. Microcalcifications also suggest
the possibility of basal cell hyperplasia since they are hardly ever seen in adenocarcinoma.
Cytologically, the occasional presence of prominent nucleoli can be concerning for
neoplasia but is allowable in basal cell hyperplasia. Demonstration of strong immunoreactivity
for basal cell markers and lack of AMACR positivity can be useful to confirm the diagnosis of
basal cell hyperplasia if doubt is persistent, although the differential diagnosis can usually be
resolved by examination of H&E-stained sections.
Finally, basal cell hyperplasia should be separated from basal cell carcinoma: Infiltrative
permeation, extraprostatic extension, perineural invasion, necrosis, and stromal desmoplasia are
characteristics of basal cell carcinoma that can help in the differential diagnostic distinction from
basal cell hyperplasia.31 Immunohistochemical marker studies for bcl2 and Ki67 may also be of
value in this separation,32 as the proliferative index in basal cell hyperplasia is low (less than
5%) and bcl2 is not overexpressed.
Radiation atypia in benign glands
Radiation atypia in benign glands is seen in follow up needle biopsy tissue or salvage
prostatectomy specimens following brachytherapy or external beam radiotherapy for prostate
carcinoma.33-36 The degree of histological alteration in benign glands depends on dose and
duration of irradiation and interval from therapy.33, 35 Radiation therapy effect may persist for
years. Changes include stromal dominance with decrease in size and number of glands,
glandular atrophy, and nuclear atypia, including nuclear enlargement and prominent nucleoli.
Basal cells, with nuclear atypia, often predominate. In the non-glandular components of the
needle biopsy, there can also be evidence of radiation effect with stromal fibrosis, slight nuclear
atypia of stromal cells, and vascular damage.
The assessment of radiation atypia vs. persistent adenocarcinoma is best made at lowpower based on architecture of the glands. A non-infiltrative glandular pattern should prompt
consideration of a diagnosis of benign glands with radiation atypia. The cytologic and nuclear
atypia induced by radiation in benign glands can mimic malignancy. In difficult cases, positive
basal cell immunostains and negative AMACR staining 37 can be extremely valuable in
establishing a diagnosis of benign atypia.
Reactive epithelial atypia
Reactive epithelial atypia may be noted in association with acute and chronic
inflammation and/or infarction. A non-infiltrative pattern and the presence of basal cells point to
a non-malignant diagnosis. Reactive squamous metaplasia adjacent to infarcts may show
prominent nucleoli,38 which should not be interpreted as an indicator of neoplasia.
Verumontanum mucosal gland hyperplasia
Although this is usually an incidental finding in radical prostatectomy specimens, it can
also be seen in needle biopsy material.39 It is characterized by a proliferation of uniform, wellcircumbscribed, closely packed, rounded glands that usually contain eosinophilic secretions.
These glands are cytologically bland and basal cells are usually identified with ease.
Small gland pattern; lesions of non-prostatic epithelial origin
Seminal vesicle and ejaculatory duct
Both the ejaculatory duct and seminal vesicle may be incidentally sampled by routine
needle biopsy; the latter is sometimes also specifically targeted for biopsy by the urologist. Both
are characterized by branching glandular structures often with numerous small glands that can
resemble adenocarcinoma. The presence of nuclear hyperchromasia, with smudged chromatin,
and scattered pleomorphic cells (sometimes striking) beyond what is seen in acinar
adenocarcinoma, as well as the presence of lipofuscin granules, occasional intranuclear
inclusions and, in the case of the seminal vesicle, a muscular wall, are all helpful clues leading
towards the correct diagnosis. However, it is important to note that the mere presence of
lipofuscin granules is not specific for seminal vesicle and ejaculatory duct epithelium, as they
can also be seen in normal, hyperplasic and carcinomatous glands.40 Difficult cases can be
resolved by IHC as seminal vesicle and ejaculatory duct epithelium is usually prostate specific
antigen (PSA) and prostatic acid phosphatase (PAP) negative (they have been reported to be
occasionally positive with polyclonal antibodies 1) and the epithelial structures are surrounded by
basal cells.
Cowper’s (bulbourethral) glands
These glands may be sampled by needle biopsy and TUR procedures. They are
characterized by closely packed, rounded mucinous glands with a central duct in a lobular
configuration. Because of their pale cytoplasm and their bland, basally-situated nuclei, Cowper’s
glands can resemble foamy-gland adenocarcinoma; however, their classic appearances are
sufficiently distinctive and should allow for an accurate diagnosis.
Mesonephric remnants
This is a rare lesion in needle biopsy and TUR material. These remnants can undergo
hyperplasia where there might be a greater chance of being misdiagnosed as prostatic
adenocarcinoma.41,42 It is histologically identical to what is seen in the female genital tract
being composed of small glandular structures lined by a single layer of cuboidal cells, usually
with dense eosinophilic intraluminal secretory material. The characteristic lack of PSA and PAP
expression 1 can be useful to confirm the diagnosis in difficult cases.
Colonic glands
Although quite frequently present in prostate needle biopsy and rarely a differential
diagnostic issue, colonic glands can be significantly distorted during the biopsy procedure and
may cause diagnostic difficulty, especially when blue-tinged mucin or prominent nuclei are
evident. 43 This problem can be compounded by the fact that colonic glands are usually negative
for basal cell markers and positive for AMACR. Identification of other colonic structures such as
the lamina propria or muscularis propria and, if necessary, a negative PSA immunostain should
be able to resolve the problem.
Nephrogenic adenoma (NA)
As noted earlier, this lesion of presumed renal tubular origin can be seen in different
locations with the urinary system including the renal pelvis, ureters, urinary bladder (most
common location) and prostatic urethra.44 The latter location is where it might cause confusion
with prostatic adenocarcinoma. Histologically, papillary structures, small tubules, or cysticallydilated tubules lined by cuboidal, low columnar or hobnail-shaped eosinophilic cells are seen.
Lesions predominantly composed of small tubules are those most likely to be confused with
prostatic adenocarcinoma. This is confounded by the fact that NA is frequently negative for basal
cell markers and not infrequently positive for AMACR, PSA and/or PAP by IHC. 1 The
characteristic histomorphologcial and immunohistochemical features, possibly supplemented by
positive PAX2 and/or PAX8 immunostains, both recently described specific markers for NA,45,
can be used to arrive at the correct diagnosis.
Large and cribriform gland patterns
(Clear cell) cribriform hyperplasia
This lesion is usually seen in the transition zone as part of benign nodular epithelial
hyperplasia.47 As its name indicates, it is characterized by a complex cribriform proliferation
composed of pale/clear cells. These cells are cuboidal to low columnar in shape, lack cytological
atypia and are surrounded by basal cells. The latter two features serve to distinguish this pattern
of hyperplasia from Gleason grade 4 cribriform adenocarcinoma. One should also be note that
normal central zone glands, occasionally sampled by needle biopsy, may also have a pattern of
growth similar to clear cell cribriform hyperplasia.
Cribriform basal cell hyperplasia
See above section on basal cell hyperplasia.
Medium to large-sized hyperplastic glands
Hyperplastic glands are characterized by complex large, often cystically-dilated glands
with luminal undulation, papillary formations or branching. For the most part, such glands can
readily be recognized as benign and easily distinguished from prostatic adenocarcinoma.
However, a variant of acinar adenocarcinoma termed pseudohyperplastic carcinoma 48 can,
especially on lower power magnification, looks very much like such benign hyperplastic glands
even in needle biopsy material.48, 49 Features of benign hyperplastic glands in comparison to
pseudohyperplastic glands include lack of crowding, lack of association with usual acinar
adenocarcinoma, benign appearing nuclei, presence of a basal cell layer by H&E and IHC, and
absence of AMACR staining. It should be noted however, that about one-quarter of
pseudohyperplastic adenocarcinomas are negative for AMACR. 50
Solid and non-glandular patterns
Granulomatous prostatitis
In addition to be being a histological mimicker of carcinoma, this lesion is also a “clinical
mimicker” as it is frequently associated with an abnormal digital rectal examination 51 and/or
elevated serum PSA levels.52 It is characterized histologically by a granulomatous inflammatory
infiltrate that is usually non-caseating and often includes giant cells. The problem with
granulomatous prostatitis is that the sheets of epithelioid (or foamy) macrophages as well as
scattered epithelial cells from remnants of ruptured prostatic ducts and acini, may all be confused
with high grade (Gleason grade 5) adenocarcinoma. The presence of giant cells, identification of
lobulocentric pattern of growth and, remembering that prostatic adenocarcinoma is rarely
associated with an inflammatory infiltrate, are usually sufficient to arrive at the correct diagnosis.
In difficult cases, lack of cytokeratin, PSA and/or PAP expression in the epithelioid histiocytes
(which usually express CD68) by IHC is diagnostic. It should also be noted that nongranulomatous, “usual prostatitis” may also be occasionally confused with prostatic
adenocarcinoma especially in the presence of significant crush artifact. 2
Prostatic xanthoma
Although rare, collection of lipid-laden foamy macrophages in the prostate can be
confused with the foamy gland variant of prostatic adenocarcinoma or, if appearing as individual
cells, with Gleason grade 5 adenocarcinoma. 53, 54 The presence of additional inflammatory cells
can be helpful, but IHC for cytokeratin (using antibody CAM 5.2), CD68, and AMACR is often
needed to resolve problematic cases. Xanthomas will be CD68 positive and negative for
cytokeratin and AMACR. It is important to note here that foamy gland carcinoma can be
negative for AMACR in up to one-third of cases.50, 55
Usually located in periprostatic soft tissues, paraganglia are occasionally sampled by
needle biopsy and may cause diagnostic concern for adenocarcinoma. 56, 57 The presence of a
nested “zellballen” growth pattern including identification of sustentacular cells and a sinusoidal
vascular pattern are key to a correct diagnosis. Immunostains for PSA, PAP (which are negative)
and positivity for neuroendocrine markers such as chromogranin can resolve difficult cases.
Signet ring-like change in non-epithelial cells
Lymphocytes 58 and prostatic stromal cells 59 (Figure 14) can rarely display a signet ringlike morphology secondary to thermal injury (in TUR specimens). It is important to be aware of
this possibility to avoid misinterpretation as high grade signet ring adenocarcinoma of the
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