BENIGN MIMICKERS

OF PROSTATE
ADENOCARCINOMA ON
NEEDLE BIOPSY AND
TR ANSURETHRAL RESEC TION
George J. Netto, MDa,b,c,*, Jonathan I. Epstein, MDa,b,c

KEYWORDS
 Mimickers of prostate cancer  Adenosis  Atrophy  Basal cell hyperplasia
 Clear cell cribriform hyperplasia  Nephrogenic adenoma  Paraganglia
 Radiation atypia  Prostatitis  Xanthoma

ABSTRACT It is helpful to categorize the histologic mimickers

of PCa into two groups, based on the grade of PCa

P
rostate needle biopsy currently is the gold
standard method for the diagnosis, man-
agement, and prognosis of prostate cancer.
Obtaining an accurate diagnosis is crucial for
pursuing proper patient management. This article
discusses histologic mimickers of prostate carci-
noma highlighting microscopic features that are
helpful to reach a correct diagnosis and emphasiz-
ing potential diagnostic pitfalls.
that could be confused with the benign mimickers
(Box 1). This article first illustrates lesions and
benign structures that mimic PCa foci displaying
architectural pattern of Gleason score 2–6 followed
by mimickers of high-grade (Gleason score 7–10)
PCa. Familiarity with and consideration of these
potential histologic mimickers will greatly help
pathologists avoid misinterpretations.1

MIMICKERS OF LOW-GRADE PROSTATE

MIMICKERS OF PROSTATE ADENOMA
Prostate needle biopsy currently is the gold stan-
dard method for the diagnosis, management,
and prognostication of prostate cancer. Obtaining
an accurate diagnosis, therefore, is crucial for
pursuing proper patient management.
Recognizing the presence of a limited focus of
carcinoma on a needle biopsy prevents a false-
negative reading. An equally important exercise by
pathologists is the recognition of the many morpho-
logic mimickers of prostate carcinoma (PCa) that
could lead to a false-positive interpretation. The
serious patient care and medicolegal implications
of a false-positive diagnosis of PCa are evident.
ADENOCARCINOMA
ADENOSIS
Overview
Adenosis is one of the most common mimickers of
PCa on needle biopsy and on transurethral resec-
tion of the prostate (TURP).2–4 Given its preferen-
tial occurrence in the transition zone, adenosis is
seen more frequently in TURP (1.6%) compared
with needle biopsy (0.8%). The relatively infre-
quent incidence of adenosis on needle biopsy
may lead to its omission from the differential diag-
nosis of small glandular lesions by a pathologist.
Furthermore, the fact that a focus of adenosis is
at times only partially sampled on needle biopsy
surgpath.theclinics.com

a
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA
b
Department of Urology, Johns Hopkins Medical Institutions, Baltimore, MD, USA
c
Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, USA
* Corresponding author.
E-mail address: gnetto1@jhmi.edu (G.J. Netto).

Surgical Pathology 1 (2008) 1–41

doi:10.1016/j.path.2008.07.008
1875-9181/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.
2 Netto & Epstein
Box 1
Histologic Mimickers of Prostate Adenocarcinoma
Benign mimickers of low-grade (Gleason score
2–6) prostate adenocarcinoma
 Adenosis (atypical adenomatous
hyperplasia)
 Atrophy
 Basal cell hyperplasia (BCH)
 Nephrogenic adenoma (NA)
 Radiation atypia
 Verumontanum mucosal gland hyperpla-
sia (VMGH)
 Mesonephric hyperplasia
 Normal structures: seminal vesicles,
colonic mucosa, and Cowper’s gland
Mimickers of high-grade (Gleason score 7–10)
prostate adenocarcinoma
 Clear cell cribriform hyperplasia
 Nonspecific granulomatous prostatitis
 Sclerosing adenosis
 Xanthoma
 Paraganglia
 Signet ring lymphocytes
Key Features
ADENOSIS
1. More frequently encountered in TURP than
needle biopsy
2. Lobular proliferation of crowded glands
3. Admixture of larger glands with papillary in-
folding and cytologically similar small glands
4. Patchy basal cells on hematoxylin-eosin
(H&E) immunostains
5. Sharing some morphologic immunohisto-
chemical features with PCa
6. Not shown to be associated with increased
risk for PCa
deprives pathologists the ability to appreciate its
characteristic lobular architecture.
Microscopic Features
On low-power examination, adenosis is character-
ized by a nodular proliferation of small glands.
Within such a nodule, larger elongated glands with
papillary infolding and branching lumina share iden-
tical nuclear and cytoplasmic features with the ad-
mixed smaller more suspicious glands (Figs. 1–5).
Fig. 1. (A) Well-circum-
scribed nodule of adeno-
sis. Note admixture of
small glands and larger
elongated glands with
occasional branching
more typical of benign
glands.
 Benign Mimickers of Prostate Adenocarcinoma 3

Fig. 1. (B) Magnified

view of well-circumscribed
nodule of adenosis, show-
ing small and elongated
glands with occasional
branching.

Fig. 2. Adenosis with

small pale-staining glands
suspicious for carcinoma
intermingled with larger,
more irregular glands
that appear benign.
4 Netto & Epstein

Fig. 3. High magnifi-

cation of glands of ad-
enosis showing focally
identifiable basal cell
layer (arrows).

Fig. 4. (A) Adenosis with

many small glands with
pale-to-clear cytoplasm
admixed with larger
glands with papillary in-
folding typical of benign
glands.
 Benign Mimickers of Prostate Adenocarcinoma 5

Fig. 4. (B) Antibodies to

high molecular weight
cytokeratin demonstrate
basal cells, verifying the
diagnosis of adenosis.
(C) Higher magnification
of biopsy (A) showing
many corpora amylacea
more typical of benign
glands.
6 Netto & Epstein
In contrast, small PCa glands usually stand out
cytologically from adjacent benign larger glands.
Table 1 lists the architectural and cytologic fea-
tures that help distinguish adenosis from low-grade
PCa (Fig. 6). To avoid misinterpretation of adeno-
sis, the constellation of histologic features in a given
lesion should outweigh the significance of any one
diagnostic feature.5 The latter is necessitated by
Table 1
Diagnostic criteria of adenosis
Adenosis
Lobular
Small glands share cytologic features with
admixed larger glands
Pale-clear cytoplasm
Medium-sized nucleoli
Blue mucinous secretions: rare
Corpora amylacea: common
Basal cells present at least in some of the glands
Fig. 5. Adenosis with occa-
sional intraluminal crystalloids.
the fact that several features are shared between
adenosis and cancer, as shown in Box 2.
Immunohistochemistry
 High molecular weight cytokeratin (CK903,
34BE12,CK5/6): patchy positivity in basal
cells.6 Lack of positivity in some of the glands
should not be misinterpreted as evidence of
Prostate Carcinoma
Haphazard growth pattern
Small glands differ from adjacent benign glands
Occasionally amphophilic cytoplasm
Occasionally large nucleoli
Blue mucinous secretions: common
Corpora amylacea: rare
Basal cells absent
 Benign Mimickers of Prostate Adenocarcinoma 7

Fig. 6. (A) Adenocarci-

noma mimicking adenosis.
(B) Higher magnification
of (A). Note single cell
layer, nuclear enlarge-
ment, and amphophilic
cytoplasm in adenocarci-
noma glands on the left
compared with benign
glands on the right.
8 Netto & Epstein

Fig. 6. (C) Higher magni-

fication of case (A). Note
presence of prominent
nucleoli and nuclear en-
largement in adenocarci-
noma glands on the right
compared with the be-
nign gland on the left.
(D) Immunostain for high
molecular weight cyto-
keratin in case shown in
(A) confirming the ab-
sence of basal cell layer
in malignant glands.
 Benign Mimickers of Prostate Adenocarcinoma
Pitfalls
ADENOSIS
! Shares several morphologic features with
low-grade PCa: crystalloids; nucleoli (medium
size); poorly formed glands and single cells
! Nodular architecture may not be appreciated
on needle biopsy sampling
! Can be alpha-methylacyl-CoA racemase (AMACR)
positive with only patchy basal cell staining
PCa as long as the negative and positive glands
share similar cytologic features.
 AMACR: P504S, a marker that is preferentially
expressed in PCa, can be focally or diffusely
expressed in adenosis in up to 10% of
cases.7
ATROPHY
Overview
Prostatic glands undergo atrophic changes as
early as the second decade of life.8 Among the
three morphologic variants of atrophy, PTAT
and PAH are the more problematic in terms of
Fig. 7. Atrophy (left core)
showing well-formed dark
glands maintaining a lobu-
lar architecture.
9
Box 2
Features shared between adenosis and prostate
carcinoma
 Crowded glands
 Crystalloids
 Medium-sized nucleoli
 Scattered poorly formed glands and single
cells
 Minimal infiltration at periphery of nodule
into surrounding glands
 AMACR immunoreactivity
mimicking PCa. PTAT is the most common mim-
icker of PCa on needle biopsy. Emerging data
point to atrophy and associated inflammation
as having a potential role in early PCa oncogen-
esis.9 Given the wide prevalence of prostatic at-
rophy, however, identification of atrophy does
not imply an increase risk for associated
malignancy.10
Microscopic Features
On low-power examination, simple atrophy and
PAH appear as acini distributed in a lobular
10 Netto & Epstein

Fig. 8. Atrophy showing

well-formed glands lined
by cells with high nu-
clear-to-cytoplasmic ratio
with relatively benign-
appearing nuclei.

Fig. 9. (A) PAH with cen-

tral dilated duct sur-
rounded by many smaller
acini.
 Benign Mimickers of Prostate Adenocarcinoma 11

Fig. 9. (B) High-power

magnification of case in
(A). Note identifiable
basal cells in (B).

Fig. 10. (A) PA mimicking

adenocarcinoma due to
the presence of small aci-
nar glands with scant
pale cytoplasm.
12 Netto & Epstein

Fig. 10. (B) Higher mag-

nification of case in (A).
Pale glands with scant cy-
toplasm merging with
fully developed atrophy
in glands to the right
and upper left corner.

Fig. 11. (A) PA. Pale glands

with scant cytoplasm merg-
ing with fully developed
atrophy.
 Benign Mimickers of Prostate Adenocarcinoma 13

Fig. 11. (B) PA.

Same case as in (A)
showing only focal
presence of basal
cells on high molec-
ular weight cytoker-
atin immunostain-
ing. The absence of
basal cells in some
of the glands in PA
should not be misin-
terpreted as sup-
porting evidence of
cancer.

configuration with typical basophilic appearance
because of relative lack of cytoplasm. Cystic
dilated glands can be encountered in simple
atrophy (Figs. 7 and 8). In PAH, close packing of
Key Features
ATROPHY
1. Variants: simple atrophy, partial atrophy
(PTAT), and postatrophic hyperplasia (PAH)
2. Preservation of lobular architecture and
scant basophilic cytoplasm help distinguish
atrophy from PCa
3. PTAT variant is most common mimicker of
PCa on needle biopsy
4. Crowded pale glands in PTAT can be over-
diagnosed as PCa
5. PTAT usually demonstrates patchy basal cells
immunostains and can be positive for AMACR
6. Atrophy has not been shown to be associ-
ated with increased risk for PCa
hyperplastic small acini is evident, at times
surrounding a feeding duct (Fig. 9).11 The nuclei in
atrophic glands occupy the full height of the lining
cells.
Although PA still may retain the lobular pattern
of PAH, it can display a more disorganized
appearance mimicking low-grade PCa glands.
The latter is compounded by the usually pale cy-
toplasm of PTAT acini (Figs. 10 and 11) and the
occasional presence of acini retaining full height
of cytoplasm and containing slightly enlarged nu-
clei with nucleoli. The latter usually are not as
prominent as the nucleoli seen in malignant
glands.12
Differential Diagnosis
Rarely, carcinoma with atrophic features can be
present on needle biopsy. Such diagnosis should
be made with great caution. Features supporting
the diagnosis of atrophic PCa include presence
of definite infiltrative pattern between larger frankly
benign glands, concomitant presence of usual,
less atrophic carcinoma, and greater degree of
cytologic atypia including very prominent nu-
cleoli. Immunohistochemical confirmation of the
absence of basal cells in the atrophic malignant
glands also should be sought (Fig. 12).
14 Netto & Epstein

Fig. 12. (A) Atrophic

prostatic adenocarci-
noma (12 ). (B) Higher
magnification and immu-
nostains of case in (A).
Note presence of nucleoli
in small acinar structures
with single cell layer and
straight inner borders.
 Benign Mimickers of Prostate Adenocarcinoma 15

Fig. 12. (C) Higher mag-

nification of case in (A).
Note presence of nucleoli
in small acinar structures
with single cell layer and
straight inner borders.
(D) High molecular
weight cytokeratin and
p63 confirm the diagno-
sis of carcinoma.
16 Netto & Epstein

Fig. 13. (A, B) Positive

expression of AMACR in
PA mimicking adenocar-
cinoma.
 Benign Mimickers of Prostate Adenocarcinoma
Differential Diagnosis
ATROPHY
 Simple atrophy should not pose diagnostic
difficulties.
 PAH rarely may enter the differential diagno-
sis of PCa. Retained lobular architecture,
basophilic scant cytoplasm, surrounding scle-
rotic collagen, and identification of feeding
duct are helpful clues to the diagnosis.
 PTAT foci lacking a lobular organization and
displaying pale cytoplasm, slight nuclear
enlargement, and occasional nucleoli can
morphologically mimic atrophic PCa. Immu-
nostains may highlight patchy basal cell layer
but can be negative in small foci.
 Adherence to strict criteria for diagnosing
atrophic PCa is crucial in the differential diag-
nosis of PTAT versus PCa
 PTAT can express AMACR
Immunohistochemistry
In difficult PTAT lesions, immunostains for basal cell
markers help highlight the presence of basal cells.
High molecular weight cytokeratins (CK903,
34BE12,CK5/6) or p63 show patchy positivity in
Fig. 14. (A) BCH with
solid and pseudocribri-
form pattern. Note piling
up of basal cells with rel-
atively clear cytoplasm
underneath an inner
more eosinophilc secre-
tory cell layer.
17
basal cells at least in some of the glands. Lack of
positivity in some glands should not be13 misinter-
preted as PCa as long as the negative and positive
glands share similar cytologic features. In a small
focus of PTAT, all the glands may be negative for
basal cell markers. AMACR: P504S can be
expressed by PTAT (Fig. 13A–B).7
Only rarely is there a need to resort to immunos-
tains to recognize simple atrophy and PAH lesions.
These two variants of atrophy demonstrate
a continuous basal layer on immunostains and
they usually are negative for AMACR.
BASAL CELL HYPERPLASIA
Overview
Basal cell proliferations in the prostate range from
BCH to basal cell carcinoma of prostate.14 BCH
commonly is seen focally involving otherwise
benign prostatic hyperplasia (BPH) nodule without
posing any diagnostic difficulty on a TURP speci-
men. Alternatively, when florid and infiltrative in
nature, especially in a limited needle biopsy
sampling, BCH can mimic PCa.15
Microscopic Features
Like the lesions discussed previously, the low-
power appearance of BCH is somewhat charac-
teristic because of its usual lobular and very
basophilic nature (Fig. 14). Additional features
18 Netto & Epstein

Fig. 14. (B) BCH charac-

teristic lobular and baso-
philic nature.

include the occasional presence of lamellar calcifi- activity and prominent nucleoli may be encoun-
cations (Fig. 15) or intracytoplasmic eosinophilic tered. The latter features may complicate its differ-
globules.16 BCH can demonstrate solid, cribri- ential from PCa further in small foci on needle
form, or pseudocribriform architecture. Mitotic sample.17 BCH with prominent nucleoli should be

Fig. 15. BCH with calc-

ifications.
 Benign Mimickers of Prostate Adenocarcinoma 19

Fig. 16. (A, B) BCH with

prominent nucleoli. The
finding is of no clinical
significance.
20 Netto & Epstein
Key Features
BASAL CELL HYPERPLASIA
1. Florid BCH can be confused with PCa when
lobular configuration is lost or is not well
demonstrated on needle sample
2. Multilayering of basal cells leads to charac-
teristic basophilic low-power appearance
3. BCH can display solid, cribriform, or pseu-
docribriform architectural patterns
4. BCH with prominent nucleoli is not a pre-
cursor of PCa and should be distinguished
from high-grade prostatic intraepithelial
neoplasia.
distinguished from high-grade prostatic intraepi-
thelial neoplasia (Fig. 16).
Differential Diagnosis
Features of BCH not typically seen in carcinoma
and features that may be present in carcinoma
are listed.
Differential Diagnosis
BASAL CELL HYPERPLASIA
Features of BCH not typically seen in carcinoma
 Solid nests
 Cells with scant cytoplasm
 Glandular lumina with atrophic luminal
cytoplasm
 Well-formed lamellar calcifications
 Intracytoplasmic eosinophilic globules
 Pseudocribriform glands
 Positivity for high molecular weight cyto-
keratin and p63
 Negative AMACR immunoreactivity
Features of BCH that may be present in
carcinoma
 Prominent nucleoli
 Cribriform architecture
 Multilayering of cells
 Mitoses
 Infiltrative pattern between benign pros-
tate glands
Immunohistochemistry
Immunostains are needed only rarely. Strong
immunostaining with basal cell markers (high
molecular weight cytokeratins and or p63) is dem-
onstrated in BCH, although these markers may be
preferentially expressed in the peripheral cells of
a gland. BCH is negative for AMACR.15
NAs typically arise in the setting of prior urothelial
injury. NA originally was believed metaplastic in ori-
gin. A recent study by Mazal and colleagues18 ana-
lyzing sex chromosomes by fluorescence in situ
hybridization in renal transplant patients who re-
ceived grafts from opposite sex donors indicated
a donor renal tubular origin for NA. This is
supported further by NA expression of PAX2, a tran-
scription factor expressed during renal
development.19
Microscopic Features
The spectrum of morphologic appearance of this
intriguing lesion includes tubular or vascular-like
structures lined by attenuated to hobnail cells to
individual cells with occasional signet ring appear-
ance. Mucinous secretions occasionally are pres-
ent. A distinct hyalinized rim may surround some
tubules. Mitotic figures are lacking. Smudged
degenerative nuclear atypia may be present. The
presence of more typical NA patterns, such as pap-
illary and tubular structures lined by a single layer of
eosinophilic cuboidal epithelium, and the associ-
ated acute and chronic inflammation should help
recognize the lesion as NA (Figs. 17 and 18).20
Key Features
NEPHROGENIC ADENOMA
1. Recently proposed renal tubule origin
2. Morphologic spectrum includes prolifera-
tion of tubules and vascular-like structures
lined by attenuated or hobnail cells with
degenerative nuclear atypia occasionally sur-
rounded by hyalinized rim
3. Arise in proximity to urothelium but can in-
filtrate muscle fibers
4. Morpholgic mimickery to PCa can be compli-
cated further by occasional prostate-specific
antigen (PSA) positivity, lack of high molecu-
lar weight/p63 staining, and strong AMACR
expression
5. Positive PAX2 immunostaining
 Benign Mimickers of Prostate Adenocarcinoma 21

Fig. 17. (A, B) Nephro-

genic Adenoma. Acinar
structures lined by a single
layer of cuboidal eosi-
nophilic cells mimicking
PCa. Note distinct base-
ment membrane rimming,
degenerative nuclear
atypia and prominent
nucleoli.
22 Netto & Epstein

Fig. 18. (A, B) Other fea-

tures of NA include the
occasional presence of
colloid-like secretory con-
tent and hobnailed nuclei
of lining epithelium.
 Benign Mimickers of Prostate Adenocarcinoma 23

BENIGN PROSTATIC TISSUE

Pitfalls
NEPHROGENIC ADENOMA
! Isolated features of NA taken out of contest
may mimic PCa (eg, signet ring–like cells,
mucinous secretion)
! Immunostaining pattern also could mimic
PCa: PSA and AMACR positive/p63 negative
! PAX2 is a reliable marker to distinguish NA
from PCa
WITH RADIATION ATYPIA
Overview
Not uncommonly, the history of prior radiation
therapy for PCa or other pelvic malignancy is not
provided to pathologists at time of prostate biopsy
examination. Familiarity with the typical changes
of radiation in benign prostatic glands, therefore,
is needed to avoid over-interpretation of such
specimens. External beam and brachytherapy
introduce somewhat similar changes in benign
prostatic glands.The cytologic changes are more

Differential Diagnosis
Isolated features of NA taken out of context can
be mistaken for PCa. Identifying other typical Key Features
morphologic features of NA and awareness RADIATION ATYPIA
of them at time overlapping immunostains
patterns of NA and PCa should help prevent
1. History of prior radiation therapy for PCa or
misinterpretation.
other pelvic malignancy frequently is not
provided to pathologist

Immunohistochemistry 2. Radiated benign glands features:

 Focal, usually weak, staining for PSA and pros- Maintain normal architecture
tate-specific acid phosphatase (PSAP) is seen Multilayered lining with streaming
in almost half of NA lesions morphology
 AMACR can be positive in more than half of
Identifiable basal cell layer
NAs21
 High molecular weight cytokeratin and p63 can Scattered cells with marked pleomorphism
be negative in more than half of NAs Degenerative smudged nuclear atypia with
 PAX2 is a reliable marker to distinguish NA from only occasional nucleoli
PCa

Fig. 19. (A, B) Radiation

therapy–induced atypia
in benign prostate gland.
Note streaming smudged
nuclear morphology and
marked nuclear pleomor-
phism. A basal cell layer
is evident surrounding
the more eosinophilic
atrophic to focally multi-
layered secretory cells.
24 Netto & Epstein

Fig. 19. (continued)

pronounced, however, and last longer (up to usually is recognizable on H&E stains. Basal
6 years) after brachytherapy.22 cells are strongly highlighted by basal cell
immunomarkers.22,23
Microscopic Features
Radiated benign glands maintain their normal ar-
chitecture. The glands are lined by multilayered SEMINAL VESICLE, COLONIC MUCOSA,
epithelial cells including scattered highly pleomor- AND COWPER’S GLANDS
phic cells (Fig. 19). The epithelial lining cells may
demonstrate a streaming, spindled appearance Overview
and contain smudged degenerative atypical nuclei The presence of tissue from adjacent normal
with only occasional nucleoli. A basal cell layer structures on prostate biopsy rarely can be
Fig. 20. SV on prostate
needle biopsy. Note SV
lumina (top) with lobular
outpouchings (bottom).
 Benign Mimickers of Prostate Adenocarcinoma 25

Fig. 21. SV on prostate

needle biopsy. Note char-
acteristic golden lipofus-
cin and marked nuclear
hyperchromasia and pleo-
morphism.

Fig. 22. SV on the tip of

prostate needle biopsy
core. SV lumina is seen to
the left with many lobu-
lar outpouchings noted.
26 Netto & Epstein

Fig. 23. (A, B) Cowper’s

glands. Note dimorphic
pattern of atrophic ducts
surrounded by mucinous
acini. Adjacent skeletal
muscle also is present.
 Benign Mimickers of Prostate Adenocarcinoma 27

Fig. 23. (C) The acini are

lined by mucin filled
goblet cells occluding
their lumina.

Fig. 24. (A) Colonic muco-

sal glands mimicking pros-
tate adenocarcinoma.
28 Netto & Epstein
confused with PCa, especially when confounded
by the presence of artifactual distortion.
Microscopic Features
Seminal vesicle (SV) tissue is characterized by the
presence of central dilated gland surrounded by
clusters of smaller glands. On needle biopsy, SV
frequently is present at the edge of the tissue
core. Identifying the dense muscularis layer
component also should bring the attention to the
SV origin of the crowded glands. The presence
of scattered epithelial cells with markedly enlarged
bizarre nuclei is another distinguishing feature
together with the typical golden brown lipofuscin
cytoplasmic pigment (Figs. 20–22).24 Benign pros-
tate glands also can have lipofuscin, yet it is not as
honey colored or globular. Rather, lipofuscin in be-
nign glands consists of small granules that are red
or violet. In difficult examples, demonstrating the
lack of basal cell layer on immunostains is helpful.
PSA and PSAP can be positive in SV glands.
Fig. 24. (B) Higher mag-
nification of case (A).
Note presence of lamina
propria and goblet cells
in the colonic mucosal
glands.
Cowper’s gland tissue is a rare encounter on
TURP and needle biopsies. It may mimic foamy
gland PCa, which typically has bland cytologic
features.17,25 Attention to the noninfiltrative lobular
architecture of mucinous glands surrounding
a central duct structure can help in proper identifi-
cation. The mucinous acini in Cowper’s gland are
lined by ovoid goblet type cells occluding acinar
lumina almost entirely (Fig. 23). Cowper’s glands
also are in skeletal muscle and not in the prostate.
In contrast, in foamy gland PCa, the lining cells
lack a goblet appearance, and dense eosinophilic
secretions are seen in glandular lumina.
Distorted colonic mucosa in transrectal needle
biopsy rarely can be mistaken for a focus of
PCa.26 The presence of mucinous secretion
and nucleoli and absence of basal cells on immu-
nostain may further lead to an overdiagnosis.
Attention to the presence of goblet cells, surround-
ing lamina propria and plasma cells, is helpful
(Fig. 24). A cautionary note is warranted related
 Benign Mimickers of Prostate Adenocarcinoma 29

Fig. 25. Mesonephric

hyperplasia. Atrophic-
appearing acini are filled
with dense colloid
secretions.

to the positive expression of AMACR in colonic
glands.
MESONEPHRIC HYPERPLASIA
Hyperplastic mesonephric remnants rarely
can be encountered in TURP specimens.27,28
Morphologically they are identical to their female
genital tract counterparts. They are composed
of atrophic-appearing glands, usually set in lob-
ules, displaying occasional hobnailed-tufted lining
(Figs. 25 and 26). Colloid secretions may be as-
sociated and glands can involve nerve and gan-
glia. PSA/PSAP negativity and positivity for
basal cell markers staining can be exploited in dif-
ficult examples.

Fig. 26. Mesonephric hy-

perplasia note small pap-
illary tufts with bland
nuclei and scant
cytoplasm.
30 Netto & Epstein

Key Features
MESONEPHRIC HYPERPLASIA
1. Atrophic-appearing glands with lobular
architecture
2. Hobnail or tufted papillary lining
3. Colloid secretions
4. PSA/PSAP negative
5. Positive basal cell staining
VERUMONTANUM MUCOSAL
GLAND HYPERPLASIA
VMGH initially was described by Gagucas and
colleagues29 as crowded proliferation of small
glandular structures in the verumontanum that
can mimic PCa. The tight lobular architecture
and the uniquely coloured rust/orange secretions
should help resolve the differential diagnosis
(Fig. 27). At times, VMGH can display papillary ar-
chitecture raising the differential of prostate duct
adenocarcinoma. Lack of cytologic atypia and
lack of cellular stratification in VGMH papillae

Fig. 27. (A, B) VMGH

with typical eosinophilic
rusty coloured secretions.
 Benign Mimickers of Prostate Adenocarcinoma
Key Features
VERUMONTANUM MUCOSAL GLAND
HYPERPLASIA
1. Small glandular proliferation and papillary
structures can mimic prostatic acinar or duc-
tal adenocarcinoma
2. Typical brown-orange coloured secretion
3. Lack of infiltrative pattern and cytologic
atypia
4. Usually obvious basal cell layer
Fig. 28. (A, B) Clear cell
cribriform hyperplasia.
31
help distinguish it from prostate duct adeno-
carcinoma.
MIMICKERS OF HIGH-GRADE
PROSTATE ADENOCARCINOMA
CLEAR CELL CRIBRIFORM HYPERPLASIA
Overview
Clear cell cribriform hyperplasia is considered by
most investigators to be a variant of BPH occur-
ring in the transition zone of the prostate. Al-
though its natural history remains unknown,
32 Netto & Epstein
Key Features
CLEAR CELL CRIBRIFORM HYPERPLASIA
1. Considered by most to be a variant of BPH
2. Transition zone location
3. Mostly seen on TURP, rare on needle biopsy
4. Prominent basal cell layer with occasional
knots
5. Bland nuclear morphology with small to
inconspicuous nucleoli
currently it is not believed pathogenetically
related to PCa.30,31
Microscopic Features
Involved glands are filled by a cribriform prolifera-
tion of clear epithelial cells with bland nuclei and
only small to inconspicuous nucleoli. Distinctly
prominent basal cell layer in some glands with oc-
casional knots of basal cells should make differen-
tiation from cribriform (Gleason score 4 1 4 5 8)
PCa possible on H&E stains in the majority of
cases (Fig. 28A–C). Immunostains to highlight
basal cells are needed only rarely (see Fig. 28D).
Fig. 28. (C) A basal cell
layer partially surround
clear cells with bland nu-
clei. Absence of nucleoli
and nuclear atypia also
help distinguish from
cribriform adenocarci-
noma. (D) High molecu-
lar weight cytokeratin
immunostaining of basal
cell layer in clear cell crib-
riform hyperplasia.
 Benign Mimickers of Prostate Adenocarcinoma 33

Pitfalls Key Features

CLEAR CELL CRIBRIFORM HYPERPLASIA NON SPECIFIC GRANULOMATOUS
PROSTATITIS (NSGP)
! Cribriform architecture and clear cell mor- 1. Most common type of granulomatous
phology mimic cribriform Gleason.score 8 PCa prostatitis
! Attention to the presence of distinct basal cell 2. Clinical and pathologic mimicker of PCa
layer in some glands and lack of nuclear aty-
pia and nucleoli help prevent misdiagnosis 3. Lobular/duct centric chronic granulomatous
inflammation
4. Epithelioid histiocytes may mimic high-
grade PCa

Another helpful clue is the lack of noncribriform 5. Intimate relation to inflamed/ruptured ducts
component of infiltrating atypical glands that and presence of multinucleated histiocytes
should be expected to be associated with the and other inflammatory cells help reaching
accurate diagnosis
majority of cribriform PCa.
6. Lack of pancytokeratin, PSA, and PSAP stain-
ing and positive staining for CD68 support
NONSPECIFIC GRANULOMATOUS PROSTATIS diagnosis in difficult examples.
Overview
With an incidence rate of up to 0.5% of adult
men,32 NSGP is the most commonly diagnosed
type of granulomatous prostatitis. More than two
thirds of patients experience a prior urinary infec-
tion. Pathogenesis, therefore, is believed a reaction
to bacterial toxins and associated glandular secre- is suggested by some investigators, given the
tions and cellular debris from ruptured inflamed high rate of NSGP occurrence in patients who
duct-acinar structures. An autoimmune etiology have HLA-DR15 phenotype.33

Fig. 29. (A) Nonspecific

granulomatous prosta-
titis. Note ruptured
inflamed duct at the cen-
ter of the lesion.
34 Netto & Epstein
Pitfalls
NON SPECIFIC GRANULOMATOUS
PROSTATITIS
! Epithelioid/foamy histiocytes of NSGP can be
confused with high-grade PCa
! NSGP lobular, duct centric nature of histio-
cytic and lymphoplasmacytic infiltrate associ-
ated with a disrupted duct is in contrast
with the more extensive and diffuse stromal
infiltration by PCa cells
! In general, PCa lacks an associated inflamma-
tory cell infiltrate
! Epithelial remnants of involved ruptured
ducts amidst infiltrate are not to be confused
with high-grade PCa cells
Microscopic Features
Early lesions consist of dilated ducts filled with
neutrophils and foamy histiocytes. As the duct
ruptures, a surrounding granulomatous inflam-
mation rich in foamy histiocytes ensue together
with a dense lymphoplasmocytic infiltrate sur-
rounding ductal-lobular units. Neutrophils and
eosinophils also may be seen admixed with oc-
casional giant cells. Epithelial remnants of prior
Fig. 29. (B) Nonspecific
granulomatous prostati-
tis. Histiocytic epithelioid
cells with prominent nu-
cleoli may be mistaken
for high-grade PCa.
ruptured ducts can be seen as individual epithe-
lial cells amidst the infiltrate and are not to be
confused with high-grade PCa cells (Fig. 29).
In difficult cases, lack of pancytokeratin, PSA,
or PSAP staining in the epithelioid histiocytes
can be illustrated by immunostains. Positive
staining for histiocytic markers (eg, CD68) also
can be of use.34
SCLEROSING ADENOSIS
Overview
Sclerosing adenosis is a rare lesion encountered
mainly in TURP specimens performed for urinary
obstruction. Rarely, it also may be sampled on
needle biopsy leading to potential overdiagnosis
as PCa.
Microscopic Features
Sclerosing adenosis is composed of a relatively
well circumscribed proliferation of well-formed
glands admixed with single epithelial cells set in
a dense background of spindle cells. The glandular
structures are similar to those seen in adenosis.
Some glands are surrounded by a distinct eosino-
philic hyaline sheath-like collarette. The lining
epithelial cells usually lack atypia. Basal cell layer
can be appreciated on H&E (Figs. 30 and 31A).
 Benign Mimickers of Prostate Adenocarcinoma 35

Fig. 30. Sclerosing ad-

enosis. Admixture of
well to poorly formed
glands with spindle cells
is noted.

Establishing the diagnosis of sclerosing adenosis
in examples demonstrating atypical features,
such as presence of crystalloids, mitotic figures,
and prominent nucleoli, requires the aid of immu-
nostains. Basal cells and spindle cells are unique
in their true myoepithelial differentiation as indi-
cated by co-expression of keratin and muscle-
specific actin (see Fig. 31B). The latter is not
expressed by basal cells in normal prostate
glands.35–38

Fig. 31. Sclerosing ad-

enosis. (A) Glandular
structures on the right
are merging with the
spindle cell component
seen on the left side.
36 Netto & Epstein
Key Features
SCLEROSING ADENOSIS
1. A rare lesion more likely to be encountered
in TURP than needle biopsies
2. Histologically composed of well-formed
glands admixed with single cells, greatly
mimicking PCa
3. Distinct hyaline sheath-like collarette may
surround some glands
4. Dense spindle cell component and basally lo-
cated cells with true myoepithelial differen-
tiation (coexpression of cytokeratin and
muscle-specific actin)
Differential Diagnosis
SCLEROSING ADENOSIS VERSUS PCA
 Sclerosing adenosis is small as opposed to
most high-grade PCa
 Dense spindle cell component is not a feature
of PCa
 Hyaline collarettes is unique to sclerosing
adenosis
 Basal and spindle cells with myoepithelial
differentiation is not seen in PCa
Fig. 31. (B) Myoepithelial
differentiation is shown,
using smooth muscle ac-
tin immunostain, in ba-
sally located cells and
occasional spindle cells.
Pitfalls
ATYPICAL FEATURES
IN SCLEROSING ADENOSIS
! Infiltrative perimeter
! Crowded glands
! Individual cells
! Prominent nucleoli
! Mitotic figures
! Crystalloids
XANTHOMA
Overview and Microscopic Features
Xanthomas are rare but potentially misleading le-
sions on small distorted needle tissue fragments.
Typical low microscopic appearance is that of
a small well-circumscribed solid nodule. Examples
that are architecturally composed of infiltrative
cords and individual cells are more troubling. Xan-
thoma cells have a uniform appearance and con-
tain abundant foamy cytoplasm and bland nuclei
without prominent nucleoli (Figs. 32 and 33). Mi-
totic activity usually is lacking.39 Mitotic figures,
however, also are rare in PCa. Immunostains
should be obtained if the possibility of xanthoma
 Benign Mimickers of Prostate Adenocarcinoma 37

Fig. 32. Xanthoma. Infil-

trating clear individual
cells could be mistaken
for Gleason pattern 5
cancer.

Fig. 33. Xanthoma.

38 Netto & Epstein
Key Features
XANTHOMA
1. Rare potential mimicker. Usually encoun-
tered in needle biopsies as a single small-
sized focus
2. Circumscribed cluster of uniform foamy cells
with bland nuclei and inconspicuous
nucleoli
3. Occasional infiltrative pattern may be
misleading
4. CD 68 positivity and negative CAM 5.2 kera-
tin staining is helpful in difficult examples
is morphologically entertained. Expression of his-
tiocytic markers, such as CD68, and lack of cyto-
keratin CAM 5.2 staining are supportive of the
diagnosis.40,41
PARAGANGLIA
Overview
Paraganglia usually are present in the extrapro-
static soft tissue in the posterolateral aspect of
the prostate.42 Less commonly they are situated
in the bladder neck smooth muscle or in lateral
prostatic stroma. They are to be distinguished
Key Features
PARAGANGLIA
1. Usually present in the extraprostatic soft
tissue
2. Cluster of cells with clear to amphophilic
cytoplasm lacking prominent nucleoli with
endocrine vascular network
3. Degenerative nuclear atypia as seen in other
neuroendocrine type cells should not be
misinterpreted
4. Paraganglia are to be considered in the dif-
ferential before a diagnosis of high-grade
PCa is rendered based on a small focus of
atypical cells that is entirely extraprostatic.
5. Neuroendocrine nature of cells and presence
of sustentacular cells can be shown on
immunostains
from high-grade PCa in the rare occurrence
when they are sampled on a needle biopsy or
TURP specimen.43
Microscopic Features
Paraganglia are composed of clusters of clear to
amphophilic cells. The cells typically contain
somewhat granular cytoplasm and lack prominent
Fig. 34. Paraganglia on
needle biopsy. Clear cell
morphology, presence of
nucleoli, and solid archi-
tecture could be mis-
taken for carcinoma.
Note highly vascular and
nested appearance.
 Benign Mimickers of Prostate Adenocarcinoma 39

Fig. 35. Paraganglia. Ba-

sophilic pigmented cyto-
plasm could offer a clue
to the diagnosis.

Fig. 36. Signet ring lym-

phocyte artifact in TURP
specimen.
40 Netto & Epstein
Differential Diagnosis
PARAGANGLIA VERSUS PCA
 Paraganglia should be considered before ren-
dering a diagnosis of high-grade PCa based
on a small focus of atypical cells that is en-
tirely extraprostatic
 Degenerative nuclear atypia and vasculariza-
tion are additional helpful clues
 Immunostains are rarely needed to demon-
strate neuroendocrine nature of cells in
question
nucleoli. The presence of moderate degenerative
nuclear atypia, as occasionally seen in neuroendo-
crine cells, should not be concerning. The rich vas-
cularization can serve as a clue (Figs. 34 and 35).
Immunostains rarely are needed to demonstrate
the neuronal nature of the cells (synaptophysin
and chromogranin positivity), presence of susten-
tacular cells (S100 positive), and lack of prostatic
differentiation (PSA and PSAP negative).
SIGNET RING CELL LYMPHOCYTES
This thermally induced artifact occasionally is seen
in TURP specimens but is not encountered in nee-
dle biopsies. When extensive, its appearance may
mimic signet ring cell variant of high-grade PCa
(Fig. 36).44
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