Small Glandular Proliferations on Needle Biopsies O

Small Glandular Proliferations on Needle Biopsies
Most Common Benign Mimickers of Prostatic Adenocarcinoma
Sent in for Expert Second Opinion
Mehsati Herawi, MD, PhD,* Anil V. Parwani, MD, PhD,
Junji Irie, MD, and Jonathan I. Epstein, MD*†‡
Abstract: The current study aimed to determine the incidence of
various benign mimickers of prostatic adenocarcinoma most
commonly encountered in a busy consultation practice. All prostate
needle biopsies from the consult service of one of the authors were
prospectively evaluated over a 7-month period. Only cases with foci
where the contributor questioned malignancy and which upon expert
review the entire case was determined to be benign were included in
this study. A total of 567 separate suspected atypical foci from 345
patients of a total of 4,046 patients (8.5%) received in consultation
were identified. Of these, 281 foci (49.5%) had immunohistochemical
(IHC) studies performed by the outside institution, which included
high molecular weight cytokeratin (HMWCK) (n = 280), alphamethylacyl-CoA racemase (AMACR) (P504s) (n = 45), and p63
(n = 34). The most common mimicker was partial atrophy (203 of
567; 35.8%). Technically adequate IHC for basal cells was performed
in 117 cases of partial atrophy with patchy or patchy/negative staining seen in 102 of 117 (87%), with the remaining 13% of cases
completely negative. A total of 15 of 19 (79%) cases of partial
atrophy were positive with AMACR. Crowded benign glands, insufficiently crowded or numerous to warrant a diagnosis of adenosis,
was the second most common mimicker (146 of 567; 25.7%).
Crowded benign glands had patchy or patchy/negative IHC for basal
cells in 66 of 81 (81%) cases with the remaining 19% of cases
completely negative. A total of 7 of 11 (64%) cases of crowded
glands were positive for AMACR. In the past, complete atrophy,
adenosis, seminal vesicle, and granulomatous prostatitis were considered common mimickers of prostate cancer on prostatic needle
biopsies. Our study shows that currently partial atrophy and crowded
benign glands are the most common benign changes causing diagnostic difficulty and prompting consultation. Negative or patchy
staining for basal cells and positive staining for AMACR may
contribute to diagnostic difficulty in these entities.
From the Departments of *Pathology, †Urology, and ‡Oncology, Johns
Hopkins University School of Medicine, Baltimore, MD. Dr. Parwani’s
current affiliation is Department of Pathology, University of Pittsburgh,
Pittsburgh, PA. Dr. Irie’s current affiliation is Department of Pathology,
Nagasaki University School of Medicine, Nagasaki, Japan.
Reprints: Jonathan I. Epstein, MD, Department of Pathology, 401 N. Broadway St., Rm 2242, Johns Hopkins Hospital, Baltimore, MD 21231
(e-mail: [email protected]).
Copyright Ó 2005 by Lippincott Williams & Wilkins
Key Words: prostate cancer, mimickers, partial atrophy, adenosis,
radiation atypia, inflammation, basal cell hyperplasia, basal cell
markers, AMACR, second opinion
(Am J Surg Pathol 2005;29:874–880)
he histopathologic interpretation of prostate needle biopsies remains the single most important tool for
establishing a diagnosis of prostate cancer. The substantial
increase in prostate needle biopsies in the prostate-specific
antigen (PSA) screening era has not only resulted in the
detection of very minute amounts of cancer but most likely
has also resulted in an increased detection of small foci of
a variety of benign lesions of the prostate. The distinction of
benign small acinar proliferations from atypical acinar proliferations suspicious for cancer is crucial, since the subsequent clinical approach is different. Biopsies harboring a
small focus of atypical glands frequently represent an
undersampled cancer and a subsequent biopsy will show
cancer in up to 50% of cases.1,6,16 In contrast, following
a diagnosis of benign mimickers of cancer, such as atrophy or
adenosis, a rebiopsy is usually not indicated. In this prospectively conducted study, we aimed to determine, based on
the necessity for referral, which benign lesions of the prostate
are currently causing the most diagnostic problems on needle
biopsy for practicing pathologists in the United States.
Case Selection
Between January 28, 2004 and August 28, 2004, a total
of 4,046 prostate needle biopsy cases were sent to one of the
authors for consultation. Of these, 345 cases (8.5%) contained
lesions of concern by the submitting pathologists that were
diagnosed upon expert review as benign. Among the 345
cases, there were a total of 567 lesions of concern on different
cores. These cases upon expert review did not have adenocarcinoma or glands suspicious for cancer or high-grade
prostatic intraepithelial neoplasia (HGPIN) in any other cores.
These cases originated from 183 centers (including commercial laboratories, community hospitals, and academic centers)
in 35 different states. All cases had routine hematoxylin and
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Small Glandular Proliferations
eosin slides available for evaluation. The mean age of men
included in this study was 61.5 years (range, 33–88 years).
Immunohistochemistry for HMWCK, p63,
For280 lesions, HMWCK-labeledsectionswere sent by the
referring pathologist along with the hematoxylin and eosin slides
for evaluation. In addition to HMWCK, stains for p63 were done
on the outside on 34 cases; as the p63 staining results were
virtually identical to those seen with HMWCK, p63 data will not
be shown. The staining pattern for HMWCK was recorded as
‘‘patchy’’ when glands in a lesion reacted with antibodies for
basal cells in a fragmented fashion, ‘‘patchy/negative’’ when the
labeling of the basal cells was fragmented in some glands and
completely absent in others within the lesion, ‘‘negative’’ when the
entire lesion failed to reveal immunoreactive basal cells, and
‘‘positive’’ when all glands showed diffuse immunoreactivity for
basal cells. Forty-five lesions had immunostains for AMACR
performed at outside institutions. The AMACR staining was
recorded ‘‘positive’’ or ‘‘negative.’’ Only staining stronger than
that of the background benign glands was considered as positive.
For the HMWCK and p63 stains, benign glands in the biopsy
served as an internal positive control.
Definitions of the Most Common Mimickers
of Prostate Adenocarcinoma
Partial atrophy is defined as prostate glands with scant
apical cytoplasm that as a consequence of more abundant
lateral cytoplasm do not appear basophilic at low magnification as compared with complete atrophy.11,24,29 Nuclei occupy
almost the full cell height, and the cytoplasm is similar to the
cytoplasm of the surrounding benign glands. Glands with
complete atrophy have a very basophilic appearance at low
magnification because of their overall scant cytoplasm and
subsequent crowded nuclei.11 We do not subclassify complete
atrophy into postatrophic hyperplasia and other patterns.2,8 By
definition, most of our cases of complete atrophy would be
considered by others as postatrophic hyperplasia as they
consisted of crowded small atrophic glands mimicking cancer,
as opposed to simple atrophy, which consists of more widely
spaced larger atrophic glands which do not resemble prostate
cancer. Adenosis is defined as a focus of very crowded small
glands suspicious for cancer admixed with more recognizably
benign glands with papillary infolding.4,11,13 Glands have pale
to clear cytoplasm with nuclei showing a lack of very prominent nucleoli. ‘‘Crowded glands’’ is defined as a focus of
benign crowded glands that unlike adenosis do not as closely
mimic adenocarcinoma of the prostate.11 ‘‘Benign glands’’ was
used when a focus was marked by the contributing pathologist
as atypical yet did not resemble prostate cancer either architecturally or cytologically upon expert review.
Of 4,046 prostate needle biopsies received in consultation in a period of 7 months, 345 cases (8.5%) contained 567
lesions of concern by the submitting pathologists that upon
expert review were identified as benign.
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FIGURE 1. Partial atrophy. Group of cystically dilated partially
atrophic glands of various sizes with mildly enlarged separated
nuclei. Scattered basal cells are noticeable.
Partial atrophy (Figs. 1–3) was the most common
mimicker of cancer identified in our study population seen in
35.8% of lesions flagged as atypical by the outside pathologist
(Table 1). The results of immunohistochemical staining
performed at the referring institutions are depicted in Table 2.
Of note, 87% of these cases showed either patchy or
patchy/negative staining for HMWCK with 13% of the lesions
totally negative, and no case with diffuse positivity. In contrast,
complete atrophy (Fig. 4), the fourth most common benign
mimicker of cancer, had in 37.5% of the lesions diffuse
positivity for HMWCK (Table 2). AMACR labeled 79% of
partial atrophy lesions.
‘‘Crowded glands’’ (Figs. 5–7) was the second most
common benign mimicker of cancer identified in 25.7% of the
lesions with similar immunohistochemical results to partial
atrophy (Table 2). ‘‘Benign glands’’ (Fig. 8), the third most
common lesion sent in for consultation, which appeared totally
normal upon expert review, had patchy, patchy/negative, or
negative staining for HMWCK in 62.5% of the lesions.
Radiation atypia, inflammatory atypia, adenosis (Fig. 9), and
basal cell hyperplasia (Fig. 10) comprised the fifth through
eighth next most commonly seen benign mimickers (Table 1).
Inflammatory atypia consisted of glands showing atypia due
to acute (14 of 26), chronic (4 of 26), or mixed acute/chronic
(8 of 26) inflammation; immunohistochemistry done at outside institutions was only performed on cases with acute
The incidence of the other less frequent benign lesions
sent in for consultation and their immunohistochemical results
are listed in Tables 1 and 2. Miscellaneous lesions consisted of
cribriform hyperplasia (n = 2), urothelial metaplasia (n = 2),
mucinous metaplasia (n = 2), nonspecific granulomatous
prostatitis (n = 2), small benign glands with pale cytoplasm
(n = 2), infarct (n = 1) (Fig. 11), paraganglioma (n = 1), colonic
mucosa (n = 1), and a tangential cut through basal cells
(n = 1).3,11,14,23,25–27
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Herawi et al
FIGURE 2. Partial atrophy. A, Disorganized partially atrophic
glands with scant cytoplasm and enlarged nuclei containing
small nucleoli. B, Staining with p63 is patchy and negative.
The differential diagnosis of small acinar proliferations
in needle biopsies of the prostate is broad and includes prostate
cancer and various benign mimickers of prostate cancer.15,17,31,32 Lesions cited as mimicking prostate cancer have
changed over the years. Whereas seminal vesicle tissue had in
the distant past been considered one of the common mimickers
of prostate cancer,18,30–32 in the current study there was not
a single case of seminal vesicle tissue that was sent in for
consultation as a result of diagnostic difficulties. In a study
published from our institution in 1995, complete atrophy and
adenosis were the most common benign lesions sent in for
consultation.12 That basal cell hyperplasia, cribriform hyperplasia, and infarcts were only infrequently seen in the current
study is not surprising as these lesions preferentially affect the
transition zone and are more frequently encountered on
transurethral resections.3,9,11,23 Radiation atypia, although seen
in only 5.6% of cases, was the fifth most common referred
lesion.5,7,22 As radiation continues to grow in popularity as
a treatment of early prostate cancer and patients treated in the
FIGURE 3. Partial atrophy. A, Haphazardly arranged small to
medium-sized glands with partial atrophy. B, Glands stained
with a cocktail containing antibodies to p63, HMWCK and
AMACR showing positive staining with AMACR and a variably
fragmented and absent basal cell layer with p63 and HMWCK.
past are followed for longer intervals where they will be at risk
for recurrence, radiation atypia can be expected in the future to
account for a greater proportion of benign cases referred in for
TABLE 1. Incidence of Lesions
Partial atrophy
Crowded glands
‘‘Benign glands’’
Complete atrophy
Radiation atypia
Inflammatory atypia
Adenosis (atypical adenomatous
Basal cell hyperplasia
No. % of Lesions
21/567 (3.7)
14/567 (2.5)
14/567 (2.5)
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TABLE 2. Immunohistochemical Results. No. (%)
Partial atrophy
Crowded glands
‘‘Benign glands’’
Complete atrophy
Radiation atypia
Inflammatory atypia
Adenosis (AAH)
Basal cell Hyperplasia
2/3 (66.7)
5/11 (45.4)
Patchy Negative
1/3 (33.3)
4/11 (36.4)
The most common benign lesion that caused difficulty
for pathologists was partial atrophy.24,29 In part, difficulty with
this entity can be attributed to its relatively recent description.
Although partial atrophy was first described in 1992,10 it was
FIGURE 4. Complete atrophy. A, Haphazardly arranged small
glands with complete atrophy with a pseudo-infiltrative
growth pattern. B, High-power of atrophic glands with
shrunken cytoplasm resulting in high nuclear to cytoplasmic
ratio and basophilic appearance.
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2/11 (18.2)
15/19 (79)
7/11 (67)
1/4 (25)
3/3 (100)
first reported in the periodic literature only in 1998.24 Partial
atrophy mimics cancer in several aspects. Architecturally,
partial atrophy consists of crowded glands often with a
disorganized growth pattern. In contrast to fully developed
atrophy, which can typically be diagnosed at scanning magnification owing to the presence of well-formed glands with
a very basophilic appearance, partial atrophy has pale cytoplasm lateral to the nuclei giving rise to pale staining glands
that more closely mimic cancer. The nuclei in partial atrophy
are slightly enlarged and irregular with occasional visible
nucleoli, and basal cells may be difficult to identify on routine
stained sections, all contributing to the difficulty in distinguishing this lesion from cancer. Clues for its correct diagnosis
include scant apical cytoplasm with nuclei extending to the full
cell height, pale lateral cytoplasm similar to the cytoplasm
seen in adjacent more recognizable benign glands, luminal
undulations as contrasted to the straight luminal borders often
seen with malignant glands, and association with regular
atrophy. An additional factor that contributes to the difficulty
in distinguishing cancer from partial atrophy is that this
mimicker may stain negative with markers for basal cells and
stain positive with AMACR. In our study population,
HMWCK performed in 117 cases of partial atrophy showed
FIGURE 5. Crowded glands. Focus of crowded benign appearing glands insufficient to establish a diagnosis of adenosis.
Herawi et al
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FIGURE 6. Collection of benign crowded glands.
patchy or patchy/negative staining in 87% of cases, with the
remaining 13% cases completely negative. Foci of partial
atrophy were positive with AMACR in 79% of cases where
stains were performed by the outside institution. The current
study is the only one that we are aware of that reports on the
basal cell and AMACR immunohistochemical staining pattern
in a series of partial atrophy. However, our cases of partial
atrophy are selected, in that only cases of partial atrophy sent
for consultation were studied and not all cases of partial
atrophy sent for review had immunohistochemical stains.
The second most common benign lesion misinterpreted
as cancer was ‘‘crowded glands.’’ Foci of crowded glands are
defined as benign glands insufficiently crowded or numerous
to warrant a diagnosis of adenosis.11 As with partial atrophy,
crowded glands in our study showed on immunostains a patchy
or patchy/negative labeling for basal cells in 81% of cases,
FIGURE 7. Crowded glands. Focus of minimally crowded small
glands. The small glands show identical nuclear and cytoplasmic features as the adjacent larger benign glands with papillary
FIGURE 8. Benign glands. Benign-appearing glands without
cytologic atypia.
FIGURE 9. Adenosis. A, Adenosis consisting of a collection of
closed-packed glands of different sizes with numerous corpora
amylacea. B, HMWCK labels the basal cells focally in a patchy
fashion; the majority of glands show negative staining.
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Am J Surg Pathol Volume 29, Number 7, July 2005
FIGURE 10. Basal cell hyperplasia. Small nucleoli may be visible
in cases of basal cell hyperplasia.
with the remaining 19% of cases completely negative. A
majority of cases of crowded glands (64%) were positive for
AMACR. In a similar vein, ‘‘benign glands’’ was the third most
common benign lesion confused with carcinoma. Although these
foci on the routinely stained sections did not resemble cancer,
62.5% of these cases demonstrated patchy, patchy/negative, or
negative staining with HMWCK. This immunohistochemical
profile causes confusion with carcinoma and was undoubtedly
one of the factors leading to these cases being referred for
consultation. That these lesions are not well-defined entities
where a pathologist can assign them a name, look them up in
a book, and read about them, also most likely contributed to the
difficulty in recognizing them as benign.
While the use of immunohistochemistry for basal cells
and more recently AMACR has aided in the diagnosis of
prostate cancer, there have also been pitfalls with their use.
Small Glandular Proliferations
Problems with the use of these markers were highlighted with
the three most common benign mimickers of cancer seen on
needle biopsy in the current study. Our work emphasizes that
pathologists must ultimately establish their diagnosis on the
hematoxylin and eosin-stained sections using immunohistochemistry as an adjunct. Pathologists must be educated on the
subtle features of partial atrophy. Patchy staining in a lesion is
diagnostic of a benign process, as long as the negatively
stained glands have the same hematoxylin and eosin morphology as those glands where basal cells are documented.
Even entirely negative staining for basal cells in a small focus
of glands can be entirely compatible with a benign process.
AMACR has been touted as being almost entirely
specific for cancer, with the exception of labeling HGPIN and
some cases of adenosis.21,28 The percentage of positive
staining with AMACR in benign glands has been reported
in previous studies to be 8% to 12%.19,20 In the current study,
both partial atrophy and crowded benign glands sent in for
consultation were positive in 79% and 67% of cases, respectively. The percentage of these cases staining for AMACR
is most likely not representative of what would be seen in these
lesions as a whole. Rather, some of these cases were most
likely sent in for consultation as a result of the AMACR
positivity. Furthermore, we did not distinguish between weak,
moderate, and strong staining and accepted any staining
stronger than the background as positive. Another potential
explanation for the differences between our study and those
citing a lower incidence of AMACR positivity in benign
glands is that our cases were stained in a variety of institutions
with varying techniques and antibodies. Nonetheless, our
study demonstrates how AMACR staining can give misleading results. In addition to highlighting the potential pitfalls
with immunohistochemical staining for HMWCK and
AMACR, the current study directs where greater educational
efforts are needed to improve the accuracy in diagnosing
prostate cancer.
FIGURE 11. Infarct. High power view of prostate glands
immediately adjacent to an infarct showing reactive immature
squamous metaplasia with enlarged hyperchromatic nuclei.
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