MIMICS OF PROSTATIC ADENOCARCINOMA
Atypical Adenomatous Hyperplasia (AAH)
Atypical adenomatous hyperplasia (AAH) is a
localized proliferation of small acini within the prostate that may be mistaken for carcinoma. Small
acinar proliferations in the prostate form a morphologic continuum ranging from benign proliferations
with minimal architectural and cytologic atypia to those in which the degree of atypia is such that they
are easily recognized as well differentiated adenocarcinoma. The proliferations are distinguished easily
at widely spaced points of the spectrum; however, no abrupt changes are apparent along the continuum.
Atypical adenomatous hyperplasia varies in incidence from 19.6% (transurethral resection specimens) to
24% (autopsy series in 20 to 40 year-old men). It can be found throughout the prostate, but is usually
present near the apex and in the transition zone and periurethral area.
AAH is distinguished from well-differentiated
carcinoma by the following: (1) inconspicuous nucleoli, (2) infrequent crystalloids; and (3) fragmented
basal cell layer as seen with basal cell-specific anti-keratin antibodies. All measures of nucleolar
size allow separation of AAH from adenocarcinoma, including mean nucleolar diameter, largest nucleolar
diameter, and percentage of nucleoli greater than 1 µm in diameter. There is apparently widespread
acceptance of Gleason's criterion of nucleolar diameter greater than 1 µm for separating
well-differentiated cancer (Gleason primary grades 1 and 2) from other proliferative lesions.
Atrophy is a common microscopic finding, consisting
of small distorted glands with flattened epithelium, hyperchromatic nuclei, and stromal fibrosis. It is
usually idiopathic, and the prevalence increases with advancing age. At low magnification, atrophy may
be confused with adenocarcinoma due to the prominent acinar architectural distortion. At high
magnification, atrophy usually lacks nuclear and nucleolar enlargement except in cases of post-atrophic
Recent reports from one institution have suggested
that atrophy be renamed prolilferative inflammatory atrophy, but there is no compelling need to change
the name; further, not all atrophy is either proliferative nor post-inflammatory, so this terminology is
erroneous and is discouraged from use.
Clusters of atrophic prostatic acini which display
proliferative epithelial changes are referred to as post-atrophic hyperplasia (PAH). PAH is at the
extreme end of the morphologic continuum of acinar atrophy which most closely mimics adenocarcinoma.
This continuum varies from mild acinar irregularity with a flattened layer of attenuated cells with scant
cytoplasm to that of PAH in which the lining cells are low cuboidal with moderate cytoplasm. There is no
sharp division in this continuum between atrophy and PAH, challenging the utility of PAH as a distinct
entity. However, the morphologic mimicry of PAH and carcinoma creates the potential for misdiagnosis,
sometimes resulting in unnecessary prostatectomy. To avoid this potentially tragic misinterpretation,
the pathologist should have an understanding of this extreme morphologic variant of atrophy. We believe
that PAH is a diagnostic category for atrophic acini which most closely mimic adenocarcinoma, recognizing
that this is merely a descriptive term.
PAH consists of a microscopic lobular cluster of 5
to 15 small acini with distorted contours reminiscent of atrophy. One or more larger dilated acini are
usually present within these small round to oval clusters, and the small acini appear to bud off of the
dilated acinus, imparting a lobular appearance to the lesion. The small acini are lined by a layer of
cuboidal secretory cells with mildly enlarged nuclei with an increased nucleus-to-cytoplasmic ratio when
compared with adjacent benign epithelial cells. The nuclei contain finely granular chromatin, and
nucleoli are usually small, although mildly enlarged nucleoli are focally present in 39% of cases. The
cytoplasm is often basophilic or finely granular to clear, and lumenal apocrine-like blebs are present in
33% of cases. Luminal mucin is occasionally present in PAH. Corpora amylacea are present in 75% of
cases of PAH, but crystalloids are rarely if ever seen.
The basal cell layer is usually present in PAH, but
is often inconspicous by routine light microscopy. Basal cell hyperplasia is rarely seen in foci of PAH.
Immunohistochemical stains for high molecular weight keratin (antibody 34ßE12) reveal a focally
fragmented basal cell layer in some cases. Adjacent prostatic acini always show at least focal atrophy.
Stromal changes are always present in PAH, ranging
from smooth muscle atrophy to dense sclerosis with compression of acini. In cases with sclerosis, the
acinar lumens were compressed and showed marked distortion. Subtyping of PAH into the lobular and
post-sclerotic subtypes is useful only to allow recognition of PAH and distinguish it from mimics such as
low grade adenocarcinoma, and we prefer not to subtype PAH. Also, PAH is often associated with patchy
chronic inflammation; infrequently, dilated acini contain luminal neutrophils.
PAH is distinguished from carcinoma by its
characteristic lobular architecture, intact or fragmented basal cell layer, inconspicuous or mildly
enlarged nucleoli, and adjacent acinar atrophy with stromal fibrosis or smooth muscle atrophy. Low grade
adenocarcinoma is the most important differential diagnostic consideration with PAH. PAH usually has a
lobular pattern on low power, similar to Gleason pattern 2 and 3 adenocarcinoma. However, the lobular
pattern is less distinct in cases with abundant stromal sclerosis, and there may be a pseudoinfiltrative
growth pattern with fibrous entrapment of acini. Nucleolar changes are also useful in separating PAH and
carcinoma, although some cases of low grade carcinoma have only patchy large nucleoli or even
micronucleoli. Mildly enlarged nucleoli may be present in PAH, but only focally, and the majority of
cells have micronucleoli. The separation of PAH from carcinoma is most difficult in needle biopsy
specimens in which only a portion of the lesion is sampled, and awareness of this entity assists in this
distinction. In about half of the biopsies containing PAH, the lesion extends to the edge of the tissue
core, indicating incomplete sampling.
Basal Cell Hyperplasia
Basal cell hyperplasia consists of a proliferation
of basal cells 2 or more cells in thickness at the periphery of prostatic acini. It sometimes appears as
small nests of cells surrounded by a few concentric layers of compressed stroma, often associated with
chronic inflammation. The nests may be solid or cystically dilated, and occasionally are punctuated by
irregular rounded luminal spaces, creating a cribriform pattern. Basal cell hyperplasia frequently
involves only part of an acinus, and sometimes protrudes into the lumen, retaining the overlying
secretory cell layer; less commonly, there is symmetric duplication of the basal cell layer at the
periphery of the acinus. The proliferation may protrude into the acinar lumen, retaining the overlying
secretory luminal epithelium. Symmetric circumferential thickening of the basal cell layer is less
frequent than eccentric thickening, and these changes do not result from tangential sectioning.
The basal cells in basal cell hyperplasia are
enlarged, ovoid or round, and plump (epithelioid), with large pale ovoid nuclei, finely reticular
chromatin, and a moderate amount of cytoplasm. Nucleoli are usually inconspicuous (less than 1 micron in
diameter) except in atypical BCH (see below). It is rarely associated with AAH.
Atypical basal cell hyperplasia is identical to
basal cell hyperplasia except for the presence of large prominent nucleoli. The nucleoli are round to
oval and lightly eosinophilic. There is chronic inflammation in the majority of cases, suggesting that
nucleolomegaly is a reflection of reactive atypia. A morphologic spectrum of nucleolar size is observed
in basal cell proliferations, and only those with more than 10% of cells exhibiting prominent nucleoli
are considered atypical.
Sclerosing adenosis of the prostate, originally
described as adenomatoid or pseudoadenomatoid tumor, consists of a benign circumscribed proliferation of
small acini set in a dense spindle cell stroma. It is an incidental finding in transurethral resection
specimens for benign prostatic hyperplasia, present in about 2% of specimens; rare cases are associated
with elevated serum PSA levels. Sclerosing adenosis is usually solitary and microscopic, but may be
multifocal and extensive.
The acini are predominantly well-formed and small
to medium size, but may form minute cellular nests or clusters with abortive lumens. The cells lining
the acini display a moderate amount of clear to eosinophilic cytoplasm, often with distinct cell margins.
The basal cell layer may be focally prominent and hyperplastic, particularly in acini thickly rimmed by
paucicellular hyalinized stroma. In some areas, the acini merge with the exuberant stroma composed of
fibroblasts and loose ground substance. There is usually no significant cytologic atypia of the
epithelial cells or stromal cells, but some cases may show moderate atypia.
Sclerosing adenosis can be distinguished from
adenocarcinoma by its dsitinctive fibroblastic stroma which is rarely seen in carcinoma; benign cytology,
with epithelial cells and stromal cells which lack the prominent nucleomegaly and nucleolomegaly usually
seen in prostatic carcinoma; hyalinized periacinar stroma occasionally seen in sclerosing adenosis;
intact basal cell layer; frequent association with BPH; and immunophenotype of S-100 protein and actin
The unique immunophenotype of sclerosing adenosis
is a valuable diagnostic clue in distinguishing it from adenocarcinoma. The basal cells show positivity
for S-100 protein and muscle specific actin, unlike normal prostatic epithelium or carcinoma;
consequently, sclerosing adenosis is considered a form of metaplasia. The basal cell layer is intact or
fragmented and discontinuous in sclerosing adenosis as demonstrated with immunohistochemical stains for
high molecular weight keratin 34ßE12, compared with absence of staining in carcinoma. Prostate specific
antigen (PSA) and prostatic acid phosphatase (PAP) are present with secretory luminal cells. Acid mucin
stain may also be of value in separating sclerosing adenosis from carcinoma; however, acid mucin is not
specific for malignancy. Ultrastructural studies confirm the presence of myoepithelial differentiation
in sclerosing adenosis, with collections of thin filaments and dense bodies.
Verumontanum Mucosal Gland Hyperplasia
This is an uncommon form of small acinar
hyperplasia which mimicks well differentiated adenocarcinoma. It is invariably small, less than 1 mm,
often multicentric, and limited anatomically to the verumontanum, utricle, ejaculatory ducts, and
adjacent prostatic urethra and ducts. The acini are small and closely packed, with an intact basal cell
layer and small uniform nuclei and inconspicuous nucleoli. The basal cells display immunoreactivity for
high molecular weight keratin, and are S-100 protein negative. This lesion is rare in needle biopsies,
and is almost never sampled in transurethral resections because of the sparing of the verumontanum by
Hyperplasia of Mesonephric Remnants
Hyperplasia of mesonephric remnants in the prostate
and periprostatic tissues is a rare and benign mimick of adenocarcinoma which is usually identified in
TURP specimens. It shares many features with mesonephric hyperplasia of the female genital tract,
including apparent infiltration of the stroma and neural spaces, lobular arrangement of small acini or
solid nests lined by a single cell layer, prominent nucleoli, and eosinophilic intratubular material.
Two histopathologic patterns have been described,
both with a lobular pattern and cuboidal cell lining. One pattern consists of small acini which contain
colloid-like material, reminiscent of thyroid follicles. The lining consists a single layer of cuboidal
cells without significant cytologic atypia. The second pattern consists of small acini or solid nests of
cells with empty lumens, reminiscent of nephrogenic metaplasia. Unlike prostate cancer, the acini of
prostatic mesonephric remnant contain a small amount of cytoplasm, and this may be the most useful
diagnostic finding. Also, the acini may be atrophic or exhibit micropapillary projections lined by
cuboidal cells. Prominent nucleoli are occasionally observed, compounding the diagnostic confusion. The
acini display immunoreactivity for keratin 34ßE12, but not for PSA and PAP. One of the original cases
was misdiagnosed as adenocarcinoma, resulting in unnecessary prostatectomy.