Mimickers of Adenocarcinoma of the Prostate
Johns Hopkins University
Table 1. Mimickers of Gleason Score 2-6 Adenocarcinoma
| Entity ||Predominant Mode of Sampling|
|Atrophy ||TURP = Needle|
|Cowper's Glands ||TURP = Needle|
|Radiation atypia ||TURP = Needle|
| || |
|Adenosis ||TURP > Needle|
|Basal cell hyperplasia ||TURP > Needle|
|Nephrogenic Adenoma ||TURP >> Needle|
| || |
|Seminal vesicles ||Needle>TURP|
|Verumontanum hyperplasia ||Needle > TURP|
| || |
|Mesonephric hyperplasia ||TURP|
| || |
|Colonic mucosa ||Needle|
One of the most common lesions that may be confused with carcinoma is adenosis (atypical adenomatous
. There is a wide spectrum in the literature in terms of the reported incidence of
adenosis on TURP, ranging from 2.2% to 19.6%
. The reason for this broad range is different
thresholds for diagnosing a focus of crowded glands as adenosis. Included within the lower threshold are
prostate specimens with foci of crowded glands, which could be considered a minimal example of adenosis,
although they do not closely mimic adenocarcinoma. At the other extreme, seen in 1.6% of benign TURPs
performed at The Johns Hopkins Hospital, adenosis closely mimics adenocarcinoma of the prostate. As
adenosis preferentially occurs within the transition zone, it is more frequently seen on TURP than on
needle biopsy, where it is seen in approximately 0.8% of cases. Adenosis is often multifocal.
The distinction of adenosis from low-grade adenocarcinoma is based on architectural and
cytologic features (Table 2).
Table 2: Diagnostic Criteria For Adenosis
|Adenosis || Low Grade Carcinoma|
Features Seen at Low and Intermediate Magnification
|Lobular growth || May be infiltrative/haphazard|
|Small crowded glands admixed with larger glands || May be pure population of small crowded glands|
Features Seen At High Magnification
|Huge (>3 micron) nucleoli absent ||Occasionally huge nucleoli present|
|Small glands share cytoplasmic and nuclear features with admixed larger benign glands ||Small glands differ from surrounding benign glands in cytoplasmic and/or nuclear features|
|Pale-clear cytoplasm ||May have amphophilic cytoplasm|
|Blue-tinged mucinous secretions Rare ||Blue-tinged mucinous secretions common|
|Corpora amylacea common ||Corpora amylacea rare|
|Occasional glands with basal cells ||Basal cells absent|
|Basal cell-specific anti-keratinantibodies label basal cells in some small glands ||Small glands are not immunoreactive with basal cell-specific anti-keratin antibodies|
In order to minimize misdiagnoses, the constellation of histologic
features seen in a lesion should outweigh the significance of any one diagnostic feature. At scanning
magnification, adenosis is characterized by a lobular proliferation of small glands. In contrast, low
grade carcinoma has a haphazard, irregular, infiltrative growth pattern. Despite the overall lobular
pattern seen in adenosis, 19% of cases reveal minimal infiltration of glands into the surrounding stroma.
Probably the most important differentiating feature of adenosis seen on H&E stain is
that within a nodule of adenosis there are elongated glands with papillary infolding and branching lumina
typical of more benign glands, yet in their nuclear and cytoplasmic features they look similar to the
adjacent small glands suspicious for carcinoma. Glands of adenocarcinoma, even in the unusual case when
the tumor is fairly lobular, shows a pure population of small crowded glands without benign architectural
features that do not merge in with adjacent larger benign glands.
At higher power, adenosis is typically composed of small glands with pale to clear
cytoplasm, as opposed to some carcinomas, which have more amphophilic cytoplasm. Occasional single cells
or poorly formed glands are not uncommon in a nodule of adenosis and probably represent tangential
sections of small glands (Table 3).
Table 3: Nondiagnostic Features In Adenosis And Carcinoma
|Features Shared in Adenosis and Cancer|
|Crowded (back-to-back glands)|
Medium-sized (<3 microns) nucleoli
Scattered poorly formed glands and single cells
Minimal infiltration at periphery of nodule
Although adenosis typically has bland appearing nuclei without
nucleoli, in 40% of cases, fairly prominent nucleoli are present, which should not lead to the diagnosis
of carcinoma . Thirty per cent of low-grade carcinomas also have either no prominent or at most rare
prominent nucleoli. These findings emphasize that, although nucleoli are generally helpful in
differentiating adenosis from adenocarcinoma, there is overlap between the two entities.
The luminal contents also may be useful in this differential diagnosis. Corpora amylacea
are commonly seen in adenosis, and are rare in carcinoma. Only 2% of cases of adenosis contain blue
intraluminal secretions visible on hematoxylin and eosin-stained sections, a feature common in low-grade
carcinomas. It is not helpful to perform special stains for mucin. Despite earlier studies' claims that
acid mucin was diagnostic of carcinoma, a later work found that 54% of foci of adenosis contained acid
mucin secretions .
Crystalloids are intraluminal structures that have been touted as distinguishing adenosis
from carcinoma. However, 18% to 39% of foci of adenosis contain crystalloids, sometimes in great number.
Crystalloids should not be used to differentiate adenosis and carcinoma (Table 3).
The presence of basal cells is the one feature seen in adenosis that is typically not seen
in carcinoma. Although basal cells may be difficult to identify within many of the glands, a flattened
basal cell layer can be seen in at least some of the glands. As long as the glands with a basal cell
layer are otherwise identical to the glands where a basal cell layer can not be identified, then the
entire lesion is benign. It is important to distinguish basal cells from adjacent fibroblasts. While
fibroblasts have elongated pointed hyperchromatic nuclei, basal cell nuclei that are recognizable in
routine sections have a more cigar-shaped ovoid contour with chromatin similar to that of the overlying
secretory cells. In foci of glandular crowding where all of the features are typical of adenosis and
there is no cytologic atypia, adenosis can be diagnosed without immunohistochemical stains even if basal
cells are not visible on routine sections.
In cases where the architectural pattern favors adenosis yet there are visible nucleoli,
the diagnosis can be clarified using immunohistochemistry for basal cells. The use of a basal cell
specific antibody to high molecular weight keratin is helpful since some glands (even though maybe only a
minority) will show a thin rim of patchy keratin immunoreactivity beneath the cuboidal or columnar
. On needle biopsy, due to the limited number of glands in question, basal cell
specific antibodies must be interpreted with caution. Because basal cell staining may be patchy in
adenosis, negative staining in a small focus of glands is not necessarily indicative of malignancy.
However, if some of the glands within a crowded glandular focus on needle biopsy demonstrate a basal cell
layer, then adenosis can be diagnosed.
Although adenosis mimics carcinoma, there is no conclusive evidence suggesting that
patients with adenosis have an increased risk of harboring or developing adenocarcinoma of the prostate
. When diagnosing adenosis, we include the following statement, "Adenosis, although mimicking
cancer, has not been shown to be associated with an increased risk of prostate cancer".
Atrophy is best diagnosed at medium to low magnification. Although the glands may appear
infiltrative, they appear invasive as a patch not as individual glands infiltrating in between larger
benign glands. At low power, atrophic glands have a very basophilic appearance. This basophilic
appearance is due to their scant cytoplasm and crowded nuclei such that at low magnification one is
merely seeing a nuclear outline of the gland. Longitudinal tangential sections of atrophic glands
results in cords of cells that can further mimic cancer. In some cases there may be associated fibrosis,
which gives the atrophic glands a more infiltrative appearance that has been termed sclerotic atrophy. A
characteristic finding in some cases is the presence of a centrally dilated atrophic gland surrounding by
fibrosis and clustered smaller glands, which has been termed "post-atrophic hyperplasia (PAH]" .
Compared to atrophy, gland-forming adenocarcinomas of the prostate typically have a greater amount of
cytoplasm so that at low magnification the neoplastic glands are not as basophilic. Atrophy may show
enlarged nuclei and prominent nucleoli, although not the huge eosinophilic nucleoli seen in some prostate
cancers. Although prominent nucleoli are more common in atrophic glands associated with inflammation, we
have also seen prominent nucleoli in atrophy without inflammation. Furthermore, the inflammation
associated with atrophy may be trivial and chronic in nature but still give rise to significant nuclear
atypia. In deciding whether an atypical focus represents carcinoma, the presence of atrophic cytoplasm
should, in general, dissuade one from diagnosing carcinoma. When there are concerns as to whether a
focus represents atrophy or adenocarcinoma, immunohistochemistry with antibodies to high molecular weight
cytokeratin can be performed to resolve the issue. Atrophy uniformly labels with high molecular weight
keratin in contrast to negative staining in adenocarcinoma.
Rarely, carcinoma with an atrophic appearance may be present on needle biopsy. The
diagnosis of carcinoma in these cases is made on: 1) a truly infiltrative process with individual small
atrophic glands situated between larger benign glands; 2) the concomitant presence of ordinary less
atrophic carcinoma; and 3) greater cytologic atypia than is seen in benign atrophy.
A variant of atrophy that may cause confusion with carcinoma is "partial atrophy" .
Partial atrophy may still retain the lobular pattern of atrophy or have more of a disorganized diffuse
appearance. Partial atrophy lacks the basophilic appearance of fully developed atrophy as the nuclei are
more spaced apart. The presence of crowded glands with pale cytoplasm may lead to an overdiagnosis of
low-grade adenocarcinoma. At higher power, however, the glands have benign features characterized by
undulating luminal surfaces with papillary infolding. Most carcinomas have more straight, even luminal
borders. In addition, the glands are partially atrophic with nuclei in areas reaching the full height of
the cytoplasm. The nuclear features in partial atrophy tend to be relatively benign without prominent
nucleoli. One should hesitate diagnosing cancer when the nuclei occupy almost the full cell height and
the cytoplasm has the same appearance as surrounding more obvious benign glands.
Basal Cell Hyperplasia
The most common form of basal cell hyperplasia consists of tubules or glands with piling
up of the basal cell layer
. In some cases of florid basal cell hyperplasia the basal cell
proliferation still retains a lobular configuration. In other instances the lobular configuration may
either be lost or not appreciated because of the fragmented nature of the transurethral resection
specimen. At low magnification, basal cell hyperplasia can be distinguished from carcinoma by its very
basaloid appearance due to multilayering of the basal cells which have scant cytoplasm. Within basal
cell hyperplasia, there is piling up of the nuclei within the lumen ranging from a single cell layer in a
few glands, to 3 to 4 cells thick in other glands, to solid nests of epithelium. Basal cell hyperplasia
may reveal focal cribriform glands. Cribriform basal cell hyperplasia in most cases resembles
back-to-back glands of basal cell hyperplasia rather than true cribriform glands. Adjacent to cribriform
basal cell hyperplasia are usually more typical individual glands of basal cell hyperplasia. Basal cell
hyperplasia is also one of the few prostatic entities that contain well-formed lamellar calcifications.
Another unique feature seen within the cells of basal cell hyperplasia is the presence of
intracytoplasmic eosinophilic globules. Basal cell lesions are preferentially located in the transition
zone and are seen on TURP, although occasionally, we have seen basal cell hyperplasia on needle biopsy.
If by light microscopy there is difficulty in distinguishing basal cell hyperplasia from
prostatic adenocarcinoma, positive staining with immunohistochemistry for basal cell specific antibodies
can identify the lesion as benign
. Basal cell hyperplasia may have prominent nucleoli, but is
otherwise identical to ordinary basal cell hyperplasia.Basal cell hyperplasia with prominent nucleoli is
distinguished from adenocarcinoma by the multilayering of its nuclei, solid nests, and atrophic
cytoplasm. There is no known association between basal cell hyperplasia showing prominent nucleoli and
either acinar adenocarcinoma or basaloid carcinoma.
Rarely, distorted fragments of colonic mucosa on transrectal biopsies of the prostate can be confused
with adenocarcinoma of the prostate. Features that can mimic prostate cancer are the presence of luminal
blue-tinged mucinous secretions and reactive/reparative atypia. The presence of goblet cells and other
features of colonic tissue, such as a potentially thickened basement membrane, lamina propria, and
muscularis should prevent a misdiagnosis. Immunohistochemistry with prostatic markers can verify the
nonprostatic nature of the lesion.
Cowper's glands can be seen on transurethral resection or on needle biopsy as a potential pitfall in
the diagnosis of prostate cancer
. The diagnosis of Cowper's glands rests on the recognition of a
noninfiltrative lobular pattern of a dimorphic population of ducts and mucinous acini in Cowper's
glands. The presence of abundant mucin-filled cytoplasm also distinguishes this lesion from carcinoma.
Although prostate cancer cytoplasm may contain neutral mucinous secretions, prostate cancers lack
abundant mucinous cytoplasm to the extent that the lumina are almost occluded. Foamy gland carcinomas
have almost as abundant cytoplasm, yet in foamy gland cancer the glands are larger and mucin stains are
In difficult cases where ducts in Cowper's glands may not be obvious, immunohistochemistry with a
panel of antibodies may be useful. In our study, prostate specific acid phosphatase (PSAP) was negative
in all cases, although the abundant cytoplasm of the acinar cells decorated focally with PSA in a
heterogeneous "clumped" fashion in four of ten cases. In contrast to prostate cancer, high molecular
weight cytokeratin (34BE12) stain the ductal epithelium, hybrid cells, and an attenuated basal layer at
the periphery of acini.
Identical to the lesion seen in the female genital tract, mesonephric hyperplasia has rarely been seen
in the prostate on either TURP or in radical prostatectomy specimens . It is distinguished from
carcinoma by the atrophic appearance of the glands, occasional papillary tufting, lack of stromal
reaction, dense colloid secretions, and negative immunoreactivity for PSA and PSAP.
Nephrogenic adenomas appear as papillary, polypoid, hyperplastic, fungating, friable, or
velvety lesions. Typically found in the bladder, 12% are seen in the urethra. Most nephrogenic adenomas
measure less than 1 cm., although they may attain dimensions as large as 7 cm. In eighteen percent of
cases, multiple lesions are identified. Lesions occurring in the prostatic urethra may be confused with
adenocarcinoma of the prostate
Nephrogenic adenomas have a broad histologic spectrum. Proliferations of small solid to
hollow tubules, lined by low columnar to cuboidal epithelial cells with eosinophilic to clear cytoplasm,
are identified in the majority of cases. Vascular-like structures with attenuated epithelium, with or
without hobnail nuclei, are the second most common pattern. Verification that these vascular-like
structures are epithelial can be accomplished with immunohistochemistry for cytokeratin, which can help
establish the correct diagnosis. Cords and individual cells with cuboidal, eosinophilic to clear
cytoplasm, polypoid or papillary configurations, and rare signet ring cell-like structures are identified
in a decreasing percent of cases. A distinguishing feature of nephrogenic adenoma is the presence of a
thickened hyaline sheath around some of the tubules, which may be enhanced with periodic acid Schiff
(PAS) stains. Cystic tubules may contain thyroid-like eosinophilic secretions Most cases of nephrogenic
adenoma are comprised of multiple histologic patterns.
Nuclear atypia, when present, appears degenerative and mitoses are either absent or rare. Nuclei are
enlarged and hyperchromatic, yet have a smudged indistinct chromatin pattern. These atypical nuclei
often reside in cells with an endothelial or hobnail appearance lining vascular-like dilated tubules.
The presence of prominent nucleoli in many cases examined is also a source of possible confusion with
prostate cancer. However, prominent nucleoli are usually only focally present within a lesion, and often
seen in association with degenerative nuclear atypia or with other features not commonly seen in prostate
cancer, such as hobnail-like cells or peritubular hyaline sheaths. Another possible source of confusion
with a malignant lesion of the prostate is the presence of blue-tinged mucinous secretions within tubular
lumina. Further mimicking prostate cancer is that in the majority of cases of nephrogenic adenoma
arising from the prostatic urethra some degree of muscle involvement is present . Features helpful
to distinguish these cases of nephrogenic adenoma from prostate cancer include the presence of more
typical nephrogenic adenoma architectural patterns in other areas of the lesion and that the lesion is
located immediately below the urothelial lining, a site unusual for prostate cancer. The presence of an
acute and/or chronic inflammatory infiltrate around and within tubular lumina of nephrogenic adenoma
structures is also not a feature of most prostate cancers.
Cytoplasmic staining for 34BE12 is found in more than one half the cases of nephrogenic adenoma, in
contrast to negative labeling in prostate cancer. Focal cytoplasmic staining and/or positive tubular
secretions for PSA and PSAP may be seen in almost half of nephrogenic adenomas, although the staining is
not as intense as typically seen in moderately-differentiated adenocarcinomas of the prostate .
The distinction between irradiated non-neoplastic prostatic glands and carcinoma is best
made on the low magnification architectural pattern of the glands
. Within the radiated normal
prostate, glands maintain their normal architectural lobular configuration. In contrast to carcinoma,
the non-neoplastic glands are separated by a modest amount of prostatic stroma. On higher magnification,
whereas glands of prostatic carcinoma are lined by a single cell layer, there is piling up of the nuclei
within irradiated normal prostate as well as an occasional recognizable basal cell layer. This piling up
of the cells in radiated benign glands frequently appears slightly spindled resembling transitional cell
metaplasia. The finding of scattered markedly atypical nuclei within well-formed acini is typical of
radiated benign glands and rare in prostate carcinoma. Prostate carcinomas that are sufficiently
differentiated to form glands rarely manifest the degree of atypia seen with radiation, and if present
would be more uniformly present in all cells. Radiated nuclei also have a degenerative, hyperchromatic
smudgy appearance as opposed to malignant prostatic nuclei that usually contain prominent nucleoli.
Irradiated non-neoplastic glands often are atrophic, in contrast to gland forming prostatic
adenocarcinomas that typically have abundant cytoplasm. It has been demonstrated that high molecular
weight cytokeratin immunohistochemistry can aid in the diagnosis of irradiated prostate by identifying
basal cells within benign radiated glands .
The recognition of seminal vesicle rests on appreciating its architectural as well as cytologic
features. Seminal vesicles are characterized by a central large dilated lumina with numerous small
glands clustered around the periphery. Often the glands appear to bud off from the central lumen.
Although on needle biopsy it may be difficult to recognize the architectural pattern of seminal vesicles
due to the limited tissue, certain features may be present. A common finding on needle biopsy of the
seminal vesicle is the dilated irregular lumen of the seminal vesicle seen at the edge of the tissue
core, where the core has fragmented as it entered the seminal vesicle lumen. Surrounding this dilated
structure are clusters of smaller glands. Recognition that the small glands suspicious for carcinoma are
all clustered around this dilated glandular structure is the first step in not overdiagnosing seminal
vesicle epithelium as carcinoma. Verification that one is dealing with seminal vesicle epithelium can
readily be accomplished at higher magnification examination. Seminal vesicle epithelium
characteristically have scattered cells showing prominent nuclear atypia
. These nuclei are
markedly enlarged with bizarre shapes and have marked hyperchromasia that often obscures nuclear
details. Despite these pleomorphic features, these nuclei lack mitotic activity. The atypia appears
degenerative in nature, similar to that which is seen with radiation atypia. The common finding within
seminal vesicles of markedly atypical nuclei present within well-formed glandular structures differs from
prostate cancer in which gland forming well to moderately-differentiated carcinomas have only slight to
moderate nuclear atypia. Even in poorly-differentiated prostatic carcinoma that lacks glandular
differentiation, one rarely sees the severe atypia that is present within scattered seminal vesicle
epithelial cells. Prominent globular golden brown lipofuscin granules are typical of seminal vesicle
epithelium. Benign prostate tissue, high grade PIN, and rarely carcinoma may contain lipofuscin pigment,
but it differs in that the granules are smaller and more red-orange or blue . If there still exists
questions as to whether the lesion is seminal vesicle epithelium or prostatic adenocarcinoma,
immunohistochemistry for high molecular weight cytokeratin will label basal cells surrounding seminal
vesicle epithelium, whereas basal cells are absent in prostate adenocarcinoma. Caution must be used with
immunohistochemistry using polyclonal antibodies to PSA as it will label seminal vesicle tissue;
monoclonal antibodies to PSA does not exhibit this cross-reactivity .
Verumontanum Mucosal Gland Hyperplasia (VMGH)
The verumontanum is situated along the posterior prostatic urethral wall and is the point at which the
utricle and ejaculatory ducts merge with the prostatic urethra. The small size and crowded nature of
verumontanum mucosal glands may simulate low-grade prostatic adenocarcinoma
. The glands of VMGH
lack the infiltrative and haphazard arrangement of the glands typically found in prostatic
adenocarcinoma. In addition, VMGH is characteristically identified adjacent to and often contiguous
with urothelium. Contents of these mucosal glands are sufficiently distinct to allow discrimination from
prostatic adenocarcinoma. Unlike prostatic adenocarcinoma, corpora amylacea are a feature typical of
VMGH. Also, in VMGH one characteristically finds distinctive brown-orange concretions. Verumontanum
mucosal glands are immunophenotypically similar to prostatic acini; thus, the secretory cells of these
mucosal glands stain positively with antibodies to prostate-specific antigen (PSA), whereas the basal
cells stain with antibodies to high molecular weight cytokeratin.
Table 4. Mimickers of Gleason Score 7-10 Adenocarcinoma
|Entity ||Predominant Mode of Sampling|
|Nonspecific granulomatous prostatitis ||TURP = Needle|
| || |
|Paraganglia ||TURP > Needle|
|Clear cell cribriform hyperplasia ||TURP > Needle|
|Sclerosing adenosis ||TURP >> Needle|
| || |
|Xanthoma ||Needle > TURP|
| || |
|Signet ring cell lymphocytes ||TURP|
Clear Cell Cribriform Hyperplasia
Clear cell cribriform hyperplasia occurs within the transition zone and is mostly seen in TURP
specimens removed for urinary obstructive symptoms, and rarely seen on needle biopsy. Although it is
considered by some to be a cribriform variant of BPH, it remains useful from the practical standpoint to
consider it as a distinct entity, as it may be confused with either prostatic intraepithelial neoplasia
(PIN) or adenocarcinoma of the prostate .
In florid cases, cribriform infiltrate the stroma diffusely mimicking cribriform Gleason
score 4+4=8 adenocarcinoma. The epithelial cells have distinctive clear cytoplasm and small bland nuclei
with inconspicuous or small nucleoli. Around many of the glands of clear cell cribriform hyperplasia is
a strikingly prominent basal cell layer, consisting of a row of cuboidal darkly staining cells beneath
the clear cells. The basal cell layer may be incomplete and in some glands may be invisible in routine
sections. Tangential sections can also result in the appearance of occasional nests of clear cells
without cribriform architecture or basal cells. Although usually unnecessary, immunostains for high
molecular weight cytokeratin can highlight the basal cell layer . The presence of basal cells around
some of the glands in clear cell cribriform hyperplasia rules out carcinoma, even though some glands with
identical nuclear and cytoplasmic features may not have an apparent basal cell layer. The glands in
clear cell cribriform hyperplasia lack cytologic atypia, in contrast to infiltrating cribriform
carcinoma. Also it is uncommon to see cribriform carcinoma unaccompanied by small infiltrating
Nonspecific Granulomatous Prostatitis (NSGP)
One of the principle entities that can be confused with high grade prostate cancer is non-specific
granulomatous prostatitis . NSGP can closely mimic cancer clinically. In a series of cases on
needle biopsy, prostatic carcinoma was suspected or considered prior to biopsy in 55% of cases .
Prostate-specific antigen levels greater than 4 ng/nL were seen in 84% of NSGP and digital rectal exam
was frequently abnormal.
Although most cases of NSGP seen on needle biopsy do not histologically resemble prostate cancer, 4%
of cases can closely resemble cancer. These cases of NSGP consists of sheets of epithelioid histiocytes
some with prominent nucleoli with abundant granular cytoplasm.The key feature to avoid a misdiagnosis of
cancer is to recognize the other inflammatory cells in nonspecific granulomatous prostatitis, such as
scattered neutrophils, lymphocytes, plasma cells, and eosinophils. The presence of scattered
multinucleated giant cells may also aid in the diagnosis of NSGP. However, despite its name,
approximately 50% of cases of NSGP lack multinucleated giant cells on needle biopsy . In contrast,
most adenocarcinomas of the prostate lack an associated inflammatory component . Although it may be
difficult to appreciate on needle biopsy specimens, NSGP initially is localized around ruptured ducts and
If there are difficulties in distinguishing NSGP from poorly differentiated adenocarcinoma,
immunohistochemistry can be utilized. These epithelioid cells will be negative for PSA, PSAP, and
pancytokeratin, and positive for various histiocytic markers .
Paraganglia have been identified in 8% of radical prostatectomies . They are usually present in
the posterolateral soft tissue exterior to the prostate. Uncommonly they may be found in the lateral
prostatic stroma or in the bladder neck smooth muscle. Rarely paraganglia may be seen on TURP or on
needle biopsy where their distinction from carcinoma must be made . They consist of clusters of
clear or amphophilic cells with fine cytoplasmic granules and a prominent vascular pattern, often
intimately related to nerves. Nucleoli are not prominent, and if nuclear atypia is present it is
degenerative in appearance as seen in endocrine lesions. Paraganglia are situated in smooth muscle, not
admixed with benign prostate glands. Although this lesion closely mimics high grade adenocarcinoma of
the prostate, the highly vascular setting along with the degenerative atypia are clues to prevent a
misdiagnosis. Also before diagnosing a small focus of high grade carcinoma on TURP or needle biopsy,
where the atypical focus appears entirely extraprostatic, paraganglia should be considered in the
differential diagnosis. Verification of the diagnosis can be accomplished with positive immunostaining
for neuroendocrine markers and S100, and negative reactivity for PSA and PSAP.
Sclerosing adenosis is found in approximately 2% of prostatic specimens
. In most cases, the
lesions are discovered incidentally in transurethral resections performed for urinary obstructive
symptoms. Usually only one or two small foci are present. Very rarely sclerosing adenosis may be seen
on needle biopsy. Sclerosing adenosis consists of a mixture of well-formed glands, single cells, and a
cellular spindle cell component.
There are several features that should prevent a misdiagnosis of malignancy.
These light microscopic features are classic for sclerosing adenosis and it is usually not
necessary to perform immunohistochemistry to clarify the diagnosis. However, immunohistochemistry is
definitive in difficult cases. Ordinary adenocarcinomas of the prostate of all grades lack basal cells
and thus high molecular weight cytokeratin immunoreactivity. Sclerosing adenosis contains a basal cell
layer around most of the glandular structures as well as among the individual cells and cords of cells.
The basal cells within sclerosing adenosis, however, are distinctive in their immunophenotypical staining
and differ from ordinary basal cells. Ordinary basal cells of the prostate show no myoepithelial cell
differentiation. They lack staining for muscle specific actin and ultrastructurally do not show
contractile elements. Within sclerosing adenosis, the basal cells show muscle specific actin positivity
consistent with myoepithelial cell differentiation. The dense spindle cell component in sclerosing
adenosis also shows partial staining with keratin and muscle specific actin consistent with myoepithelial
cell differentiation. Ultrastructural examination of several of these cases has verified their
myoepithelial differentiation. There is no known association between sclerosing adenosis and
adenocarcinoma of the prostate.
- Adenocarcinomas of the prostate composed of an admixture of glands, poorly formed glandular structures, and single cells would be assigned a high Gleason score (7 or 8). Prostatic adenocarcinomas with these scores are only rarely seen as limited foci within a TURP. The finding of only one or several small foci of a cellular lesion suspicious for high grade carcinoma should prompt a consideration of sclerosing adenosis or paraganglia. Furthermore, although sclerosing adenosis may be minimally infiltrative at its perimeter, the lesion is still relatively circumscribed in contrast to high grade prostate adenocarcinoma.
- The glandular structures in sclerosing adenosis resemble those seen in ordinary adenosis. They are composed of cells with pale to clear cytoplasm and relatively benign appearing nuclei. In many of the glandular structures, a basal cell layer can be identified on hematoxylin and eosin stained sections. This contrasts to carcinoma, where basal cells are absent.
- Sclerosing adenosis contains a dense spindle cell component that is typically lacking in adenocarcinomas. Usually, adenocarcinomas of the prostate show no apparent stromal response or at most a hypocellular fibrotic reaction.
- A rather unique feature of sclerosing adenosis is the presence of a hyaline sheath-like structure around some of the glands. The glands in ordinary adenocarcinoma lack such a collarette and have a "naked" appearance as they infiltrate the stroma.
- The relatively bland cytology may also help in distinguishing sclerosing adenosis from adenocarcinoma, although some nuclei within sclerosing adenosis may be moderately enlarged and contain prominent nucleoli.
Signet Ring Lymphocytes
TURP specimens may frequently show aggregates of degenerated lymphocytes with a signet
ring cell appearance . This finding results from thermal injury and is not seen in needle biopsy or
open prostatectomy specimens. Only rarely are these changes so prominent to be confused with signet ring
Although rare, prostatic xanthoma can be a source of diagnostic confusion, particularly with small
tissue fragments such as those obtained from needle biopsies . Features that aid in the recognition
of xanthoma include circumscription, clustering of uniform cells that lack gland formation, vacuolated
cytoplasm, and benign-appearing nuclei without prominent nucleoli; immunohistochemical studies for
histiocytic markers are confirmatory.
- Gaudin PB, Epstein JI. Adenosis of the prostate: Histologic features in transurethral resection specimens. Am J Surg Pathol 1994;18:863-870.
- Gaudin PB, Epstein JI. Adenosis of the prostate: Histologic features in needle biopsy specimens. Am J Surg Pathol 1995;19:737-747.
- Bostwick DG, Srigley J, Grignon D, et al. Atypical adenomatous hyperplasia of the prostate: morphologic criteria for its distinction from well-differentiated carcinoma. Hum Pathol 1993;24:819-832.
- Mittal BV, Amin MD, Kinare SG. Spectrum of histological lesions in 185 consecutive prostatic specimen. J Post Grad Med 1989;35:157-161.
- Srigley JR, Toth P, Hartwick RWJ. Atypical histologic patterns in cases of benign prostatic hyperplasia. Lab Invest 1989;60:69A.
- Kramer CE, Epstein JI. Nucleoli in low-grade prostate adenocarcinoma and adenosis. Hum Pathol 1993;24:618-623.
- Epstein JI, Fynheer J. Acidic mucin in the prostate: can it differentiate adenosis from adenocarcinoma? Human Pathol 1992;23:1321-1325.
- Hedrick L, Epstein JI. Use of keratin 903 as an adjunct in the diagnosis of prostate carcinoma. Am J Surg Pathol 1989;13:389-396.
- Eble JN, Epstein JI. Stage A carcinoma of the prostate. In: Pathology of the prostate, seminal vesicles, and male urethra. Bostwick DG (consultant ed.) New York: Churchill Livingstone, (Roth LM, ed.) Contemporary Issues in Surgical Pathology, 1990:61-82.
- Troncoso P, Ayala AG. Atypical small gland proliferations of the transition zone in cystoprostatectomy specimens. Mod Pathol 1994;7:85A.
- Renedo D, Poy E, Wojno KJ. Clinical significance and distinction of adenosis from low-grade adenocarcinoma of the prostate on TURP. Mod Pathol 1995;8:82A.
- Amin MB, Tamboli P, Varma M, et al. Postatrophic hyperplasia of the prostate gland: a detailed analysis of its morphology in needle biopsy specimens. Am J Surg Pathol 1999; 23:925-931.
- Oppenheimer JR, Epstein JI. Partial atrophy in prostate needle cores-another diagnostic pitfall for the surgical pathologist. Am J Surg Pathol 1998;22:440-445.
- Bennett ED, Gardner WA Jr. Embryonal hyperplasia of the prostate. The Prostate 1985;7:411-417.
- Cleary KR, Choi HY, Ayala AG. Basal cell hyperplasia of the prostate. Am J Clin Pathol 1983;80:850-854.
- Grignon DJ, Ro JY, Ordonez NG, et al. Basal cell hyperplasia, adenoid basal cell tumor, and adenoid cystic carcinoma of the prostate: An immunohistochemical study. Hum Pathol 1988;19:1425-1433.
- Epstein JI, Armas OA. Atypical basal cell hyperplasia of the prostate. Am J Surg Pathol 1992;16:1205-1214.
- Devaraj LT, Bostwick DG. Atypical basal cell hyperplasia of the prostate: Immunophenotypic profile and proposed classification of basal cell proliferations. Am J Surg Pathol 1993;17:645-659.
- Cina SJ, Silberman MA, Kahane H, et al. Diagnosis of Cowper's glands on prostate needle biopsy. Am J Surg Pathol 1997;21:550-55.
- Saboorian MH, Huffman H, Ashfaq R, et al. Distinguishing Cowper's glands from neoplastic and pseudoneoplastic lesions of prostate: Immunohistochemical and ultrastructural studies. Am J Surg Pathol 1997;21:1069-74.
- Gikas PW, Del Buono EA, Epstein JI. Florid hyperplasia of mesonephric remnants involving prostate and periprostatic tissue: Possible confusion with adenocarcinoma. Am J Surg Pathol 1993;17:454-460.
- Allan CH, Epstein JI. Nephrogenic adenoma of the prostatic urethra: A mimicker of prostate adenocarcinoma. Am J Surg Pathol 2001; 25:802-808.
- Malpica A, Ro JY, Troncoso P, et al. Nephrogenic adenoma of the prostatic urethra involving the prostate gland: a clinicopathologic and immunohistochemical study of eight cases. Hum Pathol 1994;25:390-395.
- Bostwick DG, Egbert BM, Fajardo LF. Radiation injury of the normal and neoplastic prostate. Am J Surg Pathol 1982;6:501-551.
- Brawer MK, Nagle RB, Pitts W, et.al. Keratin immunoreactivity as an aid to the diagnosis of persistent adenocarcinoma following prostatic irradiation. Cancer 1989;63:454-460.
- Magi-Galluzzi C, Sanderson H, Epstein JI. Atypia in non-neoplastic prostate glands after radiotherapy for prostate cancer: Duration of atypia and relation to type of radiotherapy. Am J Surg Pathol 27 (Feb):206-212, 2003.
- Jensen KM, Sonneland P, Madsen PO. Seminal vesicle tissue in "resectate" of transurethral resection of prostate. Urology 1983;22:20-23.
- Tsuang MT, Weiss NA, Evans AT. Transurethral resection of the prostate with partial resection of the seminal vesicle. J Urol 1981;126:615-617.
- Arias-Stella J, Takano-Moron J. Atypical epithelial changes in the seminal vesicles. Arch Pathol 1958; 66:761-766.
- Kuo T, Gomez LG. Monstrous epithelial cells in human epididymis and seminal vesicles: A pseudomalignant change. Am J Surg Pathol 1981;5:483-490.
- Brennick JB, O'Connell JX, Dickersin GR, et al. Lipofuscin pigmentation (so-called "melanosis") of the prostate. Am J Surg Pathol 1994;18:446-454.
- Varma M, Morgan M, Amin MB. Immunohistochemical detection of PSA: Comparison of monoclonal and polyclonal antibodies with implications for diagnostic pathology. Mod Pathol 2001; 14:126A.
- Gagucas RJ, Brown RW, Wheeler TM. Verumontanum mucosal gland hyperplasia. Am J Surg Pathol 1995;19:30-6.
- Gaudin PB, Wheeler TM, Epstein JI. Verumontanum mucosal gland hyperplasia in prostatic needle biopsy specimens: A mimic of low grade prostatic adenocarcinoma. Am J Clin Pathol 1995;104:620-26.
- Ayala AG, Srigley JR, Ro JY, et al. Clear cell cribriform hyperplasia of prostate: Report of ten cases. Am J Surg Pathol 1986;10:665-71.
- Frauenhoffer EE, Ro JY, El-Naggar AK, et al. Clear cell cribriform hyperplasia of the prostate: Immunohistochemical and flow cytometric study. Am J Clin Pathol 1991;95:446-453.
- Stillwell TJ, Engen DE, Farrow GM. The clinical spectrum of granulomatous prostatitis: A report of 200 cases. J Urol 1987;138:320-323.
- Oppenheimer JR, Kahane H, Epstein JI. Granulomatous prostatitis on needle biopsy. Arch Pathol Lab Med 1997;121:724-29.
- Blumenfeld W, Tucci S, Narayan P. Incidental lymphocytic prostatitis: Selective involvement with nonmalignant glands. Am J Surg Pathol 1992;16:975-981.
- Presti B, Weidner N. Granulomatous prostatitis and poorly differentiated prostate carcinoma: Their distinction with the use of immunohistochemical methods. Am J Clin Pathol 1991;95:330.
- Ostrowski ML, Wheeler TM. Paraganglia of the prostate: Location, frequency, and differentiation from prostatic adenocarcinoma. Am J Surg Pathol 1994;18:412-420.
- Kawabata K. Paraganglion of the prostate in a needle biopsy specimen: A potential diagnostic pitfall. Arch Pathol Lab Med. 1997; 121:515-516.
- Sakamoto N, Tsuneyoshi M, Enjoji M. Sclerosing adenosis of the prostate: Histopathologic and immunohistochemical analysis. Am J Surg Pathol 1991;15:660-667.
- Jones EC, Clement PB, Young RH. Sclerosing adenosis of the prostate gland: A clinicopathological and immunohistochemical study of 11 cases. Am J Surg Pathol 1991;15:1171-1180.
- Grignon DJ, Ro JY, Srigley JR, et al. Sclerosing adenosis of the prostate gland: A lesion showing myoepithelial differentiation. Am J Surg Pathol 1992;16:383-391.
- Alguacil-Garcia A. Artifactual changes mimicking signet ring cell carcinoma in transurethral prostatectomy specimens. Am J Surg Pathol 1986; 10:795-800.
- Sebo TJ, Bostwick DG, Farrow GM, et al. Prostatic xanthoma: a mimic of prostatic adenocarcinoma. Hum Pathol 1994;25:386-89.