Benign Mimics and Tumor-like Lesions in Urologic Pathology
Moderators: Dr. Mahul Amin and Dr. Liliane Boccon-Gibod
Section 2 -
Benign Mimickers of Prostatic Adenocarcinoma
John R. Srigley
Hamilton , ON , Canada
Prostatic adenocarcinoma is characterized by diverse architectural patterns and as such can be
confused with other histological patterns and processes. Histoanatomic structures such as seminal
vesicle, inflammatory and reactive conditions and pathophysiological processes including atrophy,
hyperplasia and metaplasia have protean patterns which may simulate adenocarcinoma. Most of these
lesions are readily recognized and easily separated from malignancy but they may present problems,
especially when dealing with limited sampling in thin core needle biopsies. False positive cancer
diagnosis, albeit uncommon, may be rendered in some cases leading to serious clinical, psychological and
medicolegal consequences. Prostatic biopsy pathology has been identified as a problem area which may
lead to litigation.
In my own experience, the most likely patterns giving rise to false
positive malignant calls are atrophy, post-atrophic hyperplasia, atypical adenomatous hyperplasia
(adenosis) and seminal vesicle.
In this talk, the differential diagnosis of prostatic adenocarcinoma will be discussed with emphasis
on benign mimickers as outlined in table 1. Prostatic intraepithelial neoplasia and other carcinomas may
be confused with prostatic adenocarcinoma but these topics will not be addressed. The mimickers of other
rare prostatic malignancies such as sarcoma will not be covered. The differential diagnosis of
adenocarcinoma has been detailed in several recent reviews and monographs.
Table 1: Classification of Benign Mimickers of Adenocarcinoma
- seminal vesicle/ejaculatory duct
- Cowper's gland
- rectal glands (distorted)
- verumontanum mucosal glands (hyperplasia)
- mesonephric gland remnants (hyperplasia)
- simple (lobular)
- post-atrophic hyperplasia (partial atrophy)
- usual prostatitis with preservation artifacts
- granulomatous prostatitis, non-specific
- xanthogranulomatous prostatitis (xanthoma)
- nephrogenic (adenoma)
Atypical Adenomatous Hyperplasia (Adenosis)
- basal cell hyperplasia
- benign nodular hyperplasia, small gland pattern
- (clear cell) cribriform hyperplasia
A Pattern-based Approach to Differential Diagnosis
The utility of the now famous Gleason diagram extends beyond its role as a grading tool.
It is useful in a discussion of the protean architectural patterns that are important in
diagnosing prostatic adenocarcinoma. Additionally, it provides a conceptual framework for discussing
differential diagnosis. In the Gleason diagram, there are nine patterns which can be lumped into four
major architectural categories for discussion of differential diagnosis (see table 2).
Table 2: Major Growth Patterns of Adenocarcinoma
The predominant pattern of adenocarcinoma is the small glandular one. This corresponds to Gleason
patterns 1, 2, 3A, 3B and consists of separate acini which may be tiny, small or medium in size. Most
benign mimickers enter the differential diagnosis of small acinar adenocarcinoma.
| || ||
| ||Growth Pattern ||Gleason Pattern|
|I. ||small gland ||1, 2, 3A, 3B|
|II ||large gland ||3A, 3C, 5A|
|III ||fused gland ||4A, 4B|
|IV ||solid ||5B|
| ||Growth Pattern ||Descriptors|
|I||small gland||tiny, small, medium, separate acini|
|II||large gland||simple, papillary, cribriform, comedo|
|III||fused gland ||coalescing acini, amphophilic or clear (hypernephroid)|
|IV||solid||sheets, cords, single cells|
The second major pattern is the large glandular one. Medium to large simple acini and/or papillary
and cribriform structures are seen. Central (comedo) necrosis involving round duct-like structures may
also be identified. The large gland architecture includes Gleason patterns 3A, 3C and 5A.
The third major growth pattern of adenocarcinoma is the fused glandular one which comprises Gleason
patterns 4A and 4B. The infiltrating coalesced glands may be either amphophilic (Gleason 4A) or clear
(so-called hypernephroid; Gleason 4B). A few structures and benign processes simulate this fused gland
The final major pattern of adenocarcinoma is the solid one which consists of sheets, cords and single
infiltrating cells and corresponds to a pattern 5B in the Gleason chart. Certain inflammatory lesions
may be confused with solid adenocarcinoma.
A benign mimicker may in some situations simulate more than one major pattern of adenocarcinoma. For
instance, reactive atypia involving small acini can be mistaken for small acinar carcinoma. However, if
the atypia affects medium to large glands, then the differential diagnosis is with the large gland
pattern of carcinoma.
The benign mimickers and the corresponding patterns of adenocarcinoma that may be simulated are shown
in table 3. The discussion of these entities will follow this pattern-based approach.
Table 3: Benign Mimickers in Relation to Major Growth Patterns of
Small Gland Pattern
- Seminal Vesicle
- Cowper's Gland
- Rectal glands
- Post-Atrophic Hyperplasia
- Reactive Atypia
- Mucinous Metaplasia
- Nephrogenic Metaplasia (Adenoma)
- Basal Cell Hyperplasia
- Benign Nodular Hyperplasia
- Sclerosing Adenosis, Verumontanum Mucosal Gland Hyperplasia
- Mesonephric Gland Hyperplasia
- Atypical Adenomatous Hyperplasia
Large Gland Pattern
Fused Gland Pattern
- (Clear Cell) Cribriform Hyperplasia
- Adenoid Cystic-Like Basal Cell Hyperplasia
- Reactive Atypia
- Xanthogranulomatous Inflammation (Xanthoma)
- Usual Prostatitis with preservation artifact
- Idiopathic Granulomatous Prostatitis
- Signet Ring-Like Change in Lymphocytes
Small Gland Pattern
Seminal vesicle tissue may be present in transurethral resectates or in needle biopsies, usually
unexpectedly, but sometimes as a result of specific sampling.
The seminal vesicle is
characterized by a central lumen with branching glands surrounded by smooth muscle. Commonly, the end
branching is complex resulting in numerous small glands, resulting in the so-called adenotic pattern of
seminal vesicle. This latter pattern can present problems, especially when the overall gland structure
and central lumen are not recognized. Tangential sampling of adenotic areas in a needle biopsy may
result in a small gland pattern which may cause confusion with small acinar carcinoma. 
Helpful features to distinguish adenotic seminal vesicle include the presence of nuclear hyperchromasia
and pleomorphism which at times is striking.  The degree of atypia is thought to increase
with advancing age.  Atypical cells are found centrally within the acini and they are
often more atypical than the nuclei of small acinar carcinoma. Mitoses are not identified. Small
nuclear pseudoinclusions are commonly seen. In the cytoplasm, golden brown lipofuscin pigment is usually
identified, although the amount varies from case to case. When prominent, the diagnosis of seminal
vesicle epithelium is easily supported.
It must be remembered however that lipofuscin pigment may be present in normal, hyperplastic,
preneoplastic (PIN) and carcinomatous glands.
The presence of lipofuscin pigment in
small acinar carcinoma however is rare. When the epithelial atypia and pigmentation are not prominent, a
significant diagnostic challenge may result. In problematic cases, immunohistochemistry for prostatic
specific antigen (PSA) and prostatic acid phosphatase (PAP) may be utilized. Additionally, the 34βE12
stain usually shows basal cells in seminal vesicular glands which of course are absent in small acinar
Ejaculatory duct epithelium has a similar morphology to that of the seminal vesicle. Ejaculatory
ducts however are surrounded by a band of loose fibrovascular connective tissue and lack the well formed
muscular wall of seminal vesicle. This distinction is of practical importance since the presence of
carcinoma in ejaculatory duct tissue does not indicate extraprostatic disease whereas carcinomatous
involvement of seminal vesicle proper indicates high stage disease (at least stage pT3b) and has adverse
Cowper's glands, also referred to as the bulbourethral glands are paired periurethral structures
located near the prostatic apex.
They are rarely sampled in prostatic specimens.
Cowper's glands have a lobular configuration with a central duct surrounded by tightly packed round acini
composed of cells with abundant mucinous cytoplasm. The nuclei are basally located and uniform.
Sometimes, skeletal muscle, typical of the apical region, is present in the periglandular stroma.
Cowper's glands are rarely confused with small acinar carcinoma. The duct-acinar architecture,
cytoplasmic mucin and lack of cellular atypia distinguish Cowper's glands from adenocarcinoma. In
difficult cases, special stains for mucin (mucicarmine, PAS-D) may be employed. Cowper's glands show
variable staining results for PSA and are negative for PAP.
The ductal cells exhibit
high molecular weight keratin ( 34βE12 ) staining and in some cases attenuated cells around the
periphery of the acini are also positive.  The latter cells may also exhibit smooth muscle
Another differential diagnosis of Cowper's glands is mucinous
metaplasia of prostatic acini which is usually seen in association with atrophy. 
It is common to see small amounts of rectal tissue in association with prostatic needle biopsies.
Distorted rectal glands may very rarely be mistaken for prostatic adenocarcinoma.  Rectal
tissue is usually identified in detached fragments or at the tips of prostatic cores. Sometimes rectal
glands are distorted and hyperchromatic and may contain blue-tinged luminal mucus leading to confusion
with a microfocus of prostatic adenocarcinoma. Nucleolar enlargement and mitotic activity may add to the
mimickry. Helpful features to identify distorted rectal tissue are the location of the rectal glands
usually in detached fragments, the presence of lamina propria and goblet cells and associated
inflammation. Fragments of muscularis mucosae may also be seen. In problem cases, immunohistochemical
markers may be used. Rectal glands stain negatively for PSA and cytokeratin 7 and positively for
cytokeratin 20. In most cases however careful routine microscopy allows identification of the distorted
Atrophy of prostatic glands is a common process typically but not exclusively found in older patients.
Atrophy may be seen in the young adult prostate and is commonly admixed with areas of nodular prostatic
hyperplasia.  While common in the peripheral zone, atrophy may also be seen in the central
and transition zones. Glandular atrophy is commonly associated with chronic prostatitis which may have
an active component characterized by neutrophils present in glands. Some recent evidence suggests that
prostatic atrophy may be a manifestation of chronic ischemic disease, although many examples of atrophy
are still considered idiopathic in nature.  Atrophy can also be the result of treatment
with radiation and anti-androgens.
Treatment-associated atrophy is frequently
extensive and severe and in the case of radiation may be associated with epithelial atypia.
Three major patterns of atrophy are recognized - lobular (simple), sclerotic and cystic. Combined
patterns are common. Lobular (simple) atrophy is characterized by small glands arranged in circumscribed
(lobular) nests. The orderly architecture is best appreciated on low power. In sclerotic atrophy, the
small glands are distorted by dense collagenized stroma which results in sharply angulated and irregular
shapes. The stroma often has an elastotic appearance similar to that seen in some breast conditions. At
low power, the lobular architecture is usually evident and sometimes a central dilated duct is
appreciated. The almost desmoplastic appearance of the stroma in sclerotic atrophy contrasts with low
grade, small acinar carcinoma which incites little or no stromal response. In cystic atrophy, varying
degrees of acinar dilatation are seen and usually other areas of more typical simple atrophy are found
nearby. Occasionally, atrophy may have a linear, streaming pattern in which small dark acini are lined
up in a row, seemingly permeating through stroma. This latter pattern is particularly prone to be
over-interpreted as carcinoma.
Regardless of the architectural subtype of atrophy, the cytological features are similar. The cells
are small, shrunken and dark. They have high nuclear to cytoplasmic ratios but the nuclei are uniform
and lack nuclear membrane irregularity and chromatin abnormalities. Occasionally, small chromocentres
are seen but prominent nucleoli are absent. Double layering of cells is often seen but in some instances
it may be difficult to appreciate because of the marked secretory cell atrophy. In such cases, stains
for high molecular weight keratin (34βE12) may be employed to highlight the basal cell
The important features in separating atrophy from small acinar carcinoma are the low power maintenance
of lobular architecture at least in part, uniform cytology and absence of prominent nucleoli. In some
cases, especially when the atrophy is along the edge of a biopsy or when distortion or secondary
inflammation is present, diagnosis may be difficult and special stains for high molecular weight keratin
should be employed.
In a series of secondary reviews of prostatic pathology prior to definitive treatment, atrophy was the
commonest lesion in needle biopsies to be over-interpreted as adenocarcinoma.  It should
be emphasized that carcinoma may also have an atrophic appearance and as such may be underinterpreted as
atrophy. Atrophic adenocarcinomas are composed of small dark acini usually with an irregular permeative
pattern of growth. On close inspection, there is nuclear atypia and nucleoli are usually recognized at
least focally. In some instances, 34βE12 staining may be required to distinguish the atrophic
adenocarcinoma from atrophy.
Atrophy associated with inflammation, especially active inflammation, may be particularly challenging
and one should be cautious in diagnosing carcinoma in inflamed small gland foci. Additionally, in the
setting of radiation, atrophy may be severe and may be associated with stromal fibrosis. This may result
in architectural distortion which when coupled with cytological atypia typical of radiation effects can
cause considerable diagnostic confusion. In such cases, high molecular weight keratin stains (34βE12)
are useful to separate non-neoplastic atrophic glands from residual carcinoma.
Post-atrophic hyperplasia, also referred to as partial atrophy or hyperplastic atrophy is an uncommon
histological process found in about 2-3% of prostatic needle biopsy cases.
usually found in the peripheral zone. In most cases, it is difficult to know if post-atrophic
hyperplasia represents a normal or hyperplastic focus undergoing atrophy (partial atrophy) or secondary
hyperplasia occurring in atrophic areas. Studies with proliferation markers however show increased
proliferation in areas of post-atrophic hyperplasia, thus supporting the latter hypothesis.
Post-atrophic hyperplasia consists of a combination of atrophic acini and ones that contain more
abundant clear or amphophilic cytoplasm and appear hyperplastic. The lobular acinar arrangement is
usually maintained and there is apparent budding of "neoacini" lined by cuboidal cells with clear
cytoplasm. A mixture of cells with atrophic and non-atrophic cytoplasm leads to a variety of irregular
glandular shapes including stellate ones. Some nuclear enlargement may be seen and rarely, enlarged
nucleoli are identified. The busy architecture of post-atrophic hyperplasia may cause diagnostic
confusion with adenocarcinoma, however there is generally a maintenance of some degree of lobular
architecture and basal cells are usually recognized, even at the H&E level. Prominent nucleoli in a
significant number of cells are not a typical feature of post-atrophic hyperplasia. The prudent use of
high molecular weight keratin ( 34βE12) immunostains is important in difficult cases. There is
typically a discontinuous layer of basal cells in post-atrophic hyperplasia whereas in small acinar
carcinoma, the basal cell layer is completely absent. In rare instances, luminal crystalloids and even
small amounts of basophilic luminal mucus may be present in post-atrophic hyperplasia. Caution should be
exercised whenever there is an admixture of atrophic and non-atrophic acini, especially when a lobular
pattern is not readily recognized.
The early ideas of Franks and Laivag that atrophy and post-atrophic hyperplasia are involved in the
pathogenesis of prostatic cancer were largely ignored until recently.
topographic association of prostatic carcinoma, atrophy and chronic inflammation is well known but most
investigations had been focused on other putative precursors such as prostatic intraepithelial neoplasia
(PIN) and atypical adenomatous hyperplasia (adenosis). De Marzo and coworkers have recently identified a
lesion which they refer to as proliferative inflammatory atrophy which may represent a precursor
This lesion is morphologically represented by areas of simple
atrophy and/or post-atrophic hyperplasia in which there is superimposed chronic inflammation. Using
immunohistochemistry, the above authors have identified areas of high cell proliferation in which there
is increased staining of P -glutathione s-transferase (GSTP1) and bcl-2 along with decreased staining of
the cyclin dependent kinase inhibitor p27. The findings suggest that the cells of the secretory
compartment in proliferative inflammatory atrophy have an immature secretory phenotype similar to that
seen in cells of high grade PIN and carcinoma. The authors have identified areas of atrophy merging into
high grade PIN within the same glands. They suggest that proliferative inflammatory atrophy may give
rise to carcinoma, either directly or through high grade PIN as an intermediary step. Clearly, further
investigations are required to evaluate this hypothesis. It should be stressed however that
proliferative inflammatory atrophy is a lesion which is not defined solely on the basis of the H&E
morphology but requires immunohistochemical markers of proliferation and differentiation for
There is a variation in morphological terms applied to atrophic problems and recently an International
Working Group was convened and a classification of focal atrophic lesions was proposed. 
This terminology was developed mostly to standardize studies among different research groups rather than
for specific clinical purposes (De Marzo, AM; in press).
Epithelial atypia may be seen in association with acute or chronic prostatitis and may sometimes be
present in association with prostatic ischemia (infarction). Reactive atypia can be confused with
The glands in most cases of reactive atypia are atrophic and there may
be some associated basal cell or transitional cell hyperplasia. In some cases, especially in ischemia,
the epithelium may have a squamoid appearance and frank squamous or transitional metaplasia may be
present. Mild to moderate nuclear enlargement is seen and sometimes nucleoli are prominent. The
nucleolar enlargement may actually exceed that of adenoacarcinoma.
The low power architecture, presence of basal cells and degree of cytological atypia usually allow
separation of reactive lesions from adenocarcinoma. However, adenocarcinoma may be present in areas of
prostatitis and ischemia and as such diagnostic caution should prevail.
A special situation of reactive atypia is radiation effects.
The degree of
cytological atypia in irradiated prostates may be severe with enlarged, hyperchromatic nuclei and
prominent nucleoli. The low power architectural arrangement of the atypical glands is helpful in
separating radiation atypia from residual adenocarcinoma. Other radiation associated changes include
prominent atrophy, transitional cell and squamous metaplasia, stromal fibrosis, edema and changes within
prostatic arteries. In difficult cases, immunohistochemistry for high molecular weight keratin (34βE12)
is invaluable in resolving the differential diagnosis.
Mucin producing cells are sometimes identified within prostatic glands, usually atrophic ones.
 As such, this process may enter the differential diagnosis of small acinar carcinoma. The
lobular pattern of the associated atrophy usually points to the benign nature of this lesion. Individual
mucous cells have a vacuolated appearance on H&E and highlighted by mucicarmine and PAS stains. When
there is florid mucinous metaplasia, especially in an apical location, confusion with Cowper's
(bulbourethral) glands may occur.
Nephrogenic Metaplasia (Adenoma)
Nephrogenic metaplasia (adenoma) is uncommonly encountered in the prostatic urethra, and subjacent
It may present as an exophytic (papillary) lesion or as a flat or
nodular abnormality. In most instances, there has been a previous history of trauma, instrumentation or
transurethral resection. Problems can arise when a prior transurethral resection has revealed
Nephrogenic metaplasia displays exophytic papillary and tubulocystic elements. The latter may have a
pseudoinvasive growth pattern. The acini of nephrogenic metaplasia are usually small and the cells have
scant cytoplasm. Sometimes they may have more abundant clear cytoplasm. At least focally, the tubules
may display cystic change and sometimes hobnail cells are identified. Commonly, the adjacent stroma is
both edematous and inflamed.
The small size of the acini, cystic dilatation and inflamed stroma separate nephrogenic metaplasia
from small acinar carcinoma. High molecular weight keratin ( 34βE12) is positive in some but not all
cases of nephrogenic metaplasia.  When positive, it is a helpful adjunctive test. The PSA
and PAP stains are usually negative but there may be focal positivity of tubular cells and/or
A recent study suggests that nephrogenic metaplasia (adenoma) is neither metaplastic nor neoplastic in
nature.  Molecular studies in the setting of transplantation indicates that this lesion is
truly nephrogenic in origin and results from the implantation of renal tubular cells at sites of prior
urothelial injury with subsequent proliferation of epithelial elements.
Basal Cell Hyperplasia
Basal cell hyperplasia is typically seen as part of the spectrum of nodular hyperplasia usually in
samples from the transition zone.
Recently, it has been recognized that basal cell
hyperplasia may also affect the peripheral zone.  It is usually identified in transurethral
resection specimens but may be encountered in needle biopsies. Basal cell hyperplasia may also occur in
association with atrophy, usually in the setting of anti-androgen therapy.
years, it has been recognized that basal cell hyperplasia may be confused with adenocarcinoma.
Basal cell hyperplasia is usually characterized by nodular expansion of uniform round glands
associated with a cellular stroma. It may be complete or incomplete.  There is a lack of
secretory (luminal) cell differentiation in the complete form in which solid nests of dark blue cells are
present. In the incomplete form, there are residual small lumina lined by secretory cells with clear
cytoplasm and these are surrounded by multiple layers of basal cells. In each type, the basal cells are
dark and have scant cytoplasm and display round, oval or somewhat spindled hyperchromatic nuclei.
Nucleoli are usually indistinct but in some examples of so-called atypical basal cell hyperplasia,
nucleoli may be more prominent.
Microcalcifications are present in up to half of the
cases of basal cell hyperplasia. The adjacent stroma is often hypercellular and consists of
proliferating fibroblasts and smooth muscle cells similar to those seen in usual nodular hyperplasia.
Basal cell hyperplasia is readily separated from adenocarcinoma in most cases, especially in
transurethral resectate and prostatectomy specimens. The nodular arrangement, association with ordinary
nodular hyperplasia, cellular uniformity and lack of prominent nucleoli serve to separate this condition
from cancer. It may be more difficult however in small biopsies in which part of a focus of basal cell
hyperplasia is only partially represented. In such cases, the distinction relies on the identification
of uniform cytological and nuclear features and in some instances may require immunohistochemical
staining for high molecular weight keratin (34βE12 ). 
Benign Nodular Hyperplasia, Small Gland Pattern
Benign nodular hyperplasia of prostate can have a variety of morphologies including predominantly
stromal, mixed glandular and stromal, and predominantly glandular growth patterns.
glandular elements usually consist of medium to large acini, often showing luminal papillae.
Occasionally, areas of nodular hyperplasia are composed of mainly small to medium sized, closely packed
acini with rounded lumens.
Usually basal cells are readily identified and small amounts of intervening cellular stroma are seen.
The nodular circumscription, uniform architecture, presence of basal cells and intervening stroma serve
to separate this proliferative pattern from low grade (Gleason patterns 1, 2) adenocarcinoma.
It is probably more common for adenocarcinoma to mimic benign nodular hyperplasia than the converse.
The pseudohyperplastic pattern of adenocarcinoma is composed of medium to large acini that may have a
somewhat nodular appearance on low power.
This form of carcinoma can be deceptively
bland and may only be suspected when there is a subtle disruption of the normal gland/stroma relationship
on low power. This observation can be quite difficult in thin core biopsies. On higher power, there is
an absence of basal cells and the typical nuclear features of adenocarcinoma are present. The cells
comprising this lesion are usually high cuboidal to columnar cells with abundant apical, often clear
cytoplasm. These cells resemble the appearance of the secretory cell compartment in benign nodular
hyperplasia aside from their nuclear features. The 34βE12 stain is invaluable in confirming a
diagnosis of pseudohyperplastic adenocarcinoma.
The term sclerosing adenosis of the prostate was first used by Clement in 1987 to describe an unusual
prostatic proliferative lesion which resembled to some extent sclerosing adenosis of
breast.  There had been an earlier report in which the term adenomatoid tumor was
used.  Sclerosing adenosis is an uncommon lesion largely restricted to the transition zone
and is generally an incidental finding in transurethral resectates or radical prostatectomy specimens.
It is rarely seen in needle biopsies. Several series of sclerosing adenosis have been reported.
Sclerosing adenosis is characterized by a more or less circumscribed proliferation of variably sized,
often small glands embedded in a cellular and often edematous stroma. Sometimes the lightly basophilic
stroma is recognized on low power. Tiny microacini, cords, solid clusters and single cells are seen. A
double layer is present but may be difficult to appreciate with the H&E stain. The lining cells
often have open nuclear chromatin with inconspicuous nucleoli although prominent nucleoli may be focally
present. Glandular lumens may contain crystalloids or occasionally acid mucin. A characteristic feature
is the present of a thick eosinophilic basement membrane around at least some glands.
Sclerosing adenosis is unique in that the basal cells in this condition undergo myoepithelial
metaplasia and show co-expression of both high molecular weight cytokeratin and muscle specific actin
(HHF-35).  S100 protein is also positive in these cells. The myoepithelial
differentiation has been confirmed by electron microscopic studies.
The key features distinguishing sclerosing adenosis from adenocarcinoma include the variation in gland
size and shape, thickened basement membranes and cellular stroma. Immunohistochemistry for high
molecular weight keratin ( 34βE12) and actin can be used in problematic cases.
Verumontanum Mucosal Gland Hyperplasia
Verumontanum mucosal gland hyperplasia is identified as an incidental finding in radical prostatectomy
specimens.  Fourteen percent of thirty radical prostatectomy specimens in one series
contained one or more foci of hyperplastic verumontanum mucosal glands. This process is rarely
encountered in needle biopsy specimens.  It is characterized by relatively uniform,
closely packed, round glands containing numerous corpora amylacea which may have a red or orange-brown
coloration. Basal cells are usually identified and there is a lack of nuclear features of malignancy.
In particular, prominent nucleoli are not seen. Lipofuscin pigment may be present within the cytoplasm
of glandular cells. Prostatic urethral tissue is often seen nearby and islands of transitional cell
epithelium may be present in or adjacent to the proliferating verumontanum glands. The suburethral
location, acinar and cellular uniformity, basal cells and prominent corpora amylacea allow separation of
this entity from low grade adenocarcinoma. Recently verumontanum mucosal gland hyperplasia has been
associated with atypical adenomatous hyperplasia in a radical prostatectomy series. 
Hyperplasia of Mesonephric Glands
Mesonephric gland remnants are rarely identified in prostatic specimens.
series of close to 700 transurethral resectates, 0.6% contained mesonephric remnants. 
Rarely, mesonephric glands undergo hyperplasia and are confused with adenocarcinoma. Gikas and
associates identified two cases in transurethral resection specimens that were interpreted as
adenocarcinoma which in one instance led to an unnecessary radical prostatectomy.  The
hyperplastic mesonephric glands are typically small and may have an infiltrative appearance. Sometimes
tubular dilatation, epithelial tufting and micropapillary formations are seen. They may demonstrate
perineural spread and extraprostatic extension. Mesonephric glands are lined by a single layer of
cuboidal cells. Typically the small glands contain a dense eosinophilic luminal substance which
contrasts with the loose granular eosinophilic material typical of small acinar carcinoma.
Immunohistochemistry may be helpful in difficult cases. The glands of mesonephric hyperplasia stain
negatively for PSA and PAP and often positively for high molecular weight cytokeratin (34βE12) in
contrast to adenocarcinoma which lacks 34βE12 basal cells.
Atypical Adenomatous Hyperplasia (Adenosis)
Atypical adenomatous hyperplasia (AAH) is a proliferative lesion characterized by crowded small acini,
usually forming well circumscribed nodules which often simulate the small gland pattern of
While many authors use the term "atypical adenomatous hyperplasia" others
prefer the rubric "adenosis".
AAH is a well defined entity but the term "adenosis" has
been used more loosely, even to the extent that some examples of adenosis have been interpreted by
experts as adenocarcinoma. 
AAH has been identified in 1.5 to 19.6% of transurethral resectates and in up to 33% of radical
prostatectomy specimens.  It is uncommon in needle biopsy specimens but occasionally
Most evidence associating AAH with carcinoma is circumstantial.
AAH has a
predilection for the transition zone and morphologically simulates low grade (Gleason 1, 2) carcinoma.
Examples of small acinar carcinoma arising in relationship to AAH have been reported. Additionally, the
age of patients with AAH is usually 5-10 years, less than those with carcinoma.
The basal cell specific keratin stain shows a discontinuous pattern which is intermediate between the
continuous pattern of normal prostate and the absence of basal cells in carcinoma.
Studies with tridiated thymidine, immunohistochemistry for proliferation markers (Ki67/M1B-1) and silver
staining of nucleolar-organizer regions suggest that AAH has a proliferation rate between benign prostate
hyperplasia and low grade carcinoma.
Recent molecular and phenotypic studies suggest a
possible linkage between AAH and carcinoma in the minority of cases.
While circumstantial evidence exists, there is lack of proof of a relationship between AAH and
adenocarcinoma.  It has been suggested that AAH is a precursor of some low grade transition
zone carcinomas but the lack of an increased prevalence of AAH in prostate glands with transition zone
carcinoma argues against this hypothesis.  Clearly, there is less evidence linking AAH to
carcinoma than there is high grade PIN and cancer.
The major importance of AAH is its potential for being misdiagnosed as adenocarcinoma. Foci of AAH
are usually less than 5 mm across and are characterized by a proliferation of relatively small uniform
acini, often within or adjacent to typical hyperplastic nodules. Sometimes there is a prominent
perinodular distribution of the abnormal glands. The low power architecture is reminiscent of Gleason
patterns 1 and 2 carcinoma. AAH usually has a pushing rather than infiltrating border but may show a
limited degree of infiltration. Individual glands are closely packed but separate and show no evidence
of fusion. They show some variation in size and shape and are lined by cuboidal to low columnar cells
with moderate to abundant clear or lightly eosinophilic cytoplasm. Basal cells are usually recognized at
least focally. The luminal borders are often irregular and somewhat serrated in contrast to the rigid
borders that typify small acinar carcinoma. The lumens are often empty but may contain corpora amylacea
and in some instances luminal eosinophilic crystalloids.
luminal mucus may be seen.
There is usually no stromal response but occasionally, a
fibroblastic response is identified which leads to overlap with the pattern of sclerosing adenosis.
The nuclei of atypical adenomatous hyperplasia are round to oval and there is uniform fine
chromatin.  Nucleoli may be present but they are generally small. Uncommonly, enlarged
nucleoli (>1 micron) are identified in a subset of cells. 
By immunohistochemistry, the glands of AAH exhibit strong positivity for PSA and PAP and there is
typically a discontinuous basal cell pattern with the 34βE12 stain.
Table 4: Atypical adenomatous hyperplasia versus well-differentiated adenocarcinoma
Modifed from Bostwick et al 
| ||Atypical adenomatous hyperplasia ||Carcinoma (Gleason grades 1 and 2)|
|Architectural and associated features|
| Low power |
|Circumscribed or limited infiltration |
|Circumscribed or limited infiltration |
|Nuclear size variation |
Uniform / granular
Uniform or variable
|Basal cell layer|
|H&E stain |
HMWK (34βE12) stain
The most important features in separating AAH from adenocarcinoma is the lack of significantly
enlarged nucleoli and the presence of a fragmented basal cell layer. A comparison between high and low
grade carcinoma is shown in table 4.
From a clinical perspective, AAH should be considered as a benign lesion and patients followed
conservatively. The term should not be used as a "wastebasket" for small glandular lesions that are
difficult to classify or for suspicious atypical small gland proliferations (atypical small acinar
proliferation [ASAP], glandular atypia), just below the threshold of adenocarcinoma. 
Large Gland Pattern
Clear Cell Cribriform Hyperplasia
Benign nodular hyperplasia occasionally displays areas of prominent cribriform glands. Rarely, the
cribriform process dominates the histologic picture.
Cribriform hyperplasia is
characterized by a crowded proliferation of complex glands without cytologic atypia. In most instances,
the cribriform glands have clear cytoplasm and uniform round lumina. This lesion generally has a low
power nodular appearance and intervening cellular stroma is seen. The cells comprising the central
cribriform areas are cuboidal to low columnar secretory type cells with uniform round nuclei and clear
cytoplasm. They lack nuclear atypia and nucleolar enlargement. Basal cells are prominently displayed
around the periphery.
Cribriform hyperplasia enters the differential diagnosis of both prostatic intraepithelial neoplasia
and cribriform adenocarcinoma. The distinction of cribriform hyperplasia from cribriform carcinoma is
based on the "low power" nodularity, cellular stroma, presence of basal cells and lack of significant
Adenoid Cystic-Like Basal Cell Hyperplasia
While most forms of basal cell hyperplasia are characterized by relatively small nests of basal cells,
the incomplete form of basal cell hyperplasia may be composed of medium to large glands with a complex
cribriform pattern, sometimes with cyst formation and squamous metaplasia.
process rarely enters the differential diagnosis of cribriform carcinoma. Some of these cases have been
termed adenoid basal cell tumor or even basal cell carcinoma. The presence of typical areas of basal
cell hyperplasia, lack of significant infiltration and absence of cytological atypia favor adenoid
cystic-like basal cell hyperplasia over cribriform carcinoma.
Reactive Atypia in Large Glands
Medium to large glands may display reactive atypia in the setting of inflammation, ischemia and
Such processes may lead to glandular distortion and nuclear atypia which
sometimes results in a pattern that may be confused with large gland patterns of adenocarcinoma. The
most helpful features to distinguish reactive atypia from malignancy is the recognition of the associated
inciting factor such as inflammation, infarction or other radiation effects, and the maintenance of the
basal cell compartment. The atypia associated with reactive conditions may result in nuclei that appear
hyperchromatic and somewhat degenerate. In some cases, the nucleolar enlargement associated with the
reactive state may be more prominent and more uniform than that seen with adenocarcinoma. The low power
architecture and presence of a residual basal cell layer sometimes requiring confirmation with the 34βE12
stain are the best clues to the benign nature of this condition.
Fused Gland Pattern
Paraganglionic tissue may be encountered within prostatic and periprostatic tissue, usually the
Paraganglia are characterized by small, solid nests of cells with clear or
amphophilic cytoplasm, often with a "zellballen" arrangement. There is a delicate background network of
capillaries. The nuclei are often hyperchromatic but nucleoli and other features of adenocarcinoma are
not seen. The islands of paraganglionic tissue are separated by fibrous stroma. Paraganglionic tissue
can simulate the fused gland pattern of adenocarcinoma (Gleason 4). If the cytoplasm of the
paraganglionic tissue is amphophilic, it may look like Gleason pattern 4A and if clear may look like
Gleason pattern 4B. Cases in needles biopsies are quite rare. A more common issue is the
over-interpretation of extraprostatic paraganglionic tissue in radical prostatectomy specimens leading to
spurious over-staging of organ-confined cancer. Additionally, the interpretation of paraganglionic
tissue as adenocarcinoma may lead to a grading inaccuracy. When a Gleason grade 3 tumor is encountered
and accompanying paraganglionic tissue is interpreted as Gleason grade 4 tumor, the resultant score would
be inaccurately recorded as 7 instead of the correct score of 6. In problematic cases, special stains
determining prostatic origin (PSA, PAP) and stains for neuroendocrine cells (chromogranin, synaptophysin)
should be employed.
Xanthogranulomatous Prostatitis (Xanthoma)
Collections of lipid laden macrophages in the prostate may cause diagnostic confusion with the
hypernephroid pattern of adenocarcinoma (Gleason 4B).
usually have small uniform nuclei within conspicuous nucleoli and are commonly admixed with other types
of inflammatory cells. In some instances, there is almost a pure population of foam cells which can lead
to considerable diagnostic confusion. The problem is compounded by the fact that some hypernephroid
carcinomas do not show the typical nuclear features of malignancy. They may have small dark nuclei
without prominent nucleoli. In rare cases, immunohistochemistry utilizing stains for epithelial and
prostatic cells (cytokeratin, PSA, PAP) and histiocytes (CD68) is required to resolve the diagnostic
Malakoplakia of the prostate is a rare infiltrative lesion characterized by diffuse sheets of
histiocytes, usually admixed with other inflammatory cells including lymphocytes, plasma cells and
In the early phase of malakoplakia when von Hansemann histiocytes
predominate, the lesion may simulate carcinoma, especially Gleason pattern 4. The lack of any acinar
differentiation and admixed inflammatory infiltrate along with the typical Michaelis-Gutmann bodies will
lead to a correct diagnosis. The absence of cytokeratins and prostatic epithelial markers along with the
presence of CD68 staining may resolve difficult diagnostic problems.
Occasionally, needle biopsies with prostatitis of the usual type may cause diagnostic problems.
This is especially true when there is poor preservation and mechanical (crush) artifacts.
In some cases, immunohistochemical stains (keratins, leukocyte common antigens) are required in order to
resolve a differential diagnosis.
Non-specific Granulomatous Prostatitis
Granulomatous prostatitis commonly results in a prostate gland that feels firm to hard and clinically
In biopsy samples, especially needle biopsies, florid
non-specific granulomatous prostatitis may simulate carcinoma.
The association of
the inflammation with ducts may not be seen and when the inflammatory process is diffuse, it may raise
the suspicion of high grade (Gleason 5) carcinoma. The problem is amplified if poor preservation or
mechanical artifacts are present. The recognition of the inflammatory nature of the cells along with the
association of giant cells and fibrosis are helpful features. In difficult cases, immunohistochemistry
for cytokeratins, prostatic epithelial markers and lymphohistiocytic markers may be used. Granulomatous
prostatitis associated with specific infections such as fungus and tuberculosis, BCG-associated
granulomas and the procedural associated granulomas (palisading granulomas) do not usually cause problems
in the differential diagnosis of adenocarcinoma.
Degenerative Changes in Lymphocytes and Stromal Cells
Lymphocytes and sometimes stromal cells may undergo degenerative changes which result in a signet
If the change is prominent, the pattern can resemble high
grade adenocarcinoma composed of individual signet ring cells. The artifactual signet ring-like pattern,
while initially described in transurethral resectates, may be found in needle biopsies. In the series of
47 cases, these "atypical" cells were prominent in 3 cases and rare in 11 cases. It is very important to
be aware of this phenomenon and not to overinterpret such cells as being malignant. In difficult cases,
immunohistochemical stains can be used to confirm the non-epithelial nature of the cells.
There are a wide variety of patterns and processes that may be confused with one or more of the
diverse patterns of prostatic adenocarcinoma. In general, recognition of this differential diagnosis
coupled with careful routine microscopy will lead to a correct diagnosis. In some instances however,
ancillary studies aimed at identifying prostatic basal cells (34βE12 , CK5/6), prostatic secretory
cells (PSA, PAP, CD57), neuroendocrine cells (chromogranin, synaptophysin) and inflammatory cells (LCA,
CD68) may be required to resolve a diagnostic dilemma. The new marker α-m ethylacyl-CoA racemase
(P504S) appears to be of value in supporting a diagnosis of adenocarcinoma, especially when one is
dealing with small foci.
Awareness of the differential diagnosis of prostatic adenocarcinoma is especially important in the
context of diagnosing limited carcinoma in small biopsy samples. It is important to always be aware of
the potential of false positive cancer diagnosis when looking at prostatic biopsies and to utilize
appropriate consultation and ancillary studies to arrive at a confident and correct diagnosis.
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