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- Original Article -
IAssociations among benign prostate hypertrophy, atypical
adenomatous hyperplasia and latent carcinoma of the prostate
Konstantinos Stamatiou1,2, Alevizos
Alevizos1,2,3, Mohamed
Natzar2, Constantinos Mihas3, Anargiros
Mariolis3, Emmanouel
Michalodimitrakis4, Fragiskos
Sofras1
1Department of Urology, University Hospital, Medical School, University of Crete, Heraklion 71110, Greece
2Department of Urology, Tzaneion General Hospital, Piraeus18536, Greece
3Department of Medical Research, Health Center of Vyronas, Athens 16231, Greece
4Department of Forensic Sciences, University Hospital, Medical School, University of Crete, Heraklion 71110, Greece
Abstract
Aim: To investigate the frequency of atypical adenomatous hyperplasia (AAH) and its associations with benign
prostate hypertrophy (BPH) and latent histological carcinoma of the prostate (LPC) in autopsy material.
Methods: Two hundred and twelve prostate specimens obtained from autopsy material were subjected to whole mount analysis
in an attempt to investigate the associations among BPH, AAH and LPC.
Results: Most histological carcinomas and AAH lesions were found in enlarged prostates with intense hypertrophy. No statistically significant relation was found
between BPH and the main characteristics of LPC, such as tumor volume, histological differentiation and biological
behavior. Our data regarding multi-focal tumors showed a tendency for multi-focal carcinomas to develop in larger
prostates, and a tendency of AAH lesions to develop in larger prostates. No statistically significant relation was found
between AAH and LPC. Conclusion: There seems not any causative aetiopathogenetical or topographical relation
between AAH lesions and prostate adenocarcinoma. AAH lesion seems to be a well-defined mimicker of prostatic
adenocarcinoma, and the reported association of AAH with prostatic carcinoma could probably be an
epiphenomenon. (Asian J Androl 2007 Mar; 9: 229_233)
Keywords: atypical adenomatous hyperplasia; histological prostate cancer; benign prostate hypertrophy
Correspondence to: Dr Konstantinos Stamatiou, Department of Urology, University Hospital, Medical School, University of Crete,
Heraklion 71110, Greece.
Tel: +30-210-760-8051 Fax: +30-210-760-8053
E-mail: stamatiouk@gmail.com
Received 2005-12-27 Accepted 2006-04-20
DOI: 10.1111/j.1745-7262.2007.00187.x
1 Introduction
Atypical adenomatous hyperplasia (AAH; also termed
adenosis), is a localized proliferative lesion consisting of
small amounts of atypical epithelial cells arranged in
irregular glandular patterns. AAH lesions usually appear
as compact, well-circumscribed nodules, in which the
basal cell layer is often indistinguishable or discontinued.
Although being of uncertain biologic significance and
easily mistaken for Gleason pattern 1 or 2 prostate
cancer [1], AAH lesions can be easily distinguished
from carcinomas by the degree of nucleolar enlargement [2]. The occurrence rate of AAH is not known,
and its aetiopathological associations with benign
prostate hypertrophy (BPH) and latent carcinoma of the
prostate (LPC) have not been completely clarified. We
performed 212 consecutive autopsies in an attempt to
investigate the frequency of AAH and its associations with
BPH and LPC. To our knowledge, there are few
up-to-date published necropsy studies. Of those few studies,
some described significant differences of the occurrence
of AAH, histological BPH and LPC [3_7].
2 Materials and methods
2.1 Study population
The study included 212 men between 30 and 98 years
of age who died between August 2002 and August 2004,
of diseases other than clinically diagnosed carcinoma of
the prostate. All of them were of Greek origin. Cases
suspected with a history of prostate cancer, cases with
abnormal digital rectal examination in the pre-necropsy
examination and cases found with macroscopic foci of
cancer in any organ were excluded.
2.2 Sample removal and processing
The whole prostate and seminal vesicles were removed with accuracy. The specimen was weighed and
measured in three dimensions (width × height × length).
The surface of the two lobes was colored in different
colors and fixed in acetic acid. A 10% formalin solution
was injected uniformly (per cm²) into the gland and the
specimen was then immersed in formalin solution allowed
to fix for 3 days. Seminal vesicles were removed and
sectioned through the base. Base and apex were also
removed by transversal sections and the slices were cut
at 4-mm intervals. The rest of the two lobes were
divided and sectioned at 4-mm intervals perpendicular to
the long axis of the gland. Pieces were postfixed,
re-sectioned, dehydrated, cleared in xylene and embedded
in paraffin. Every piece was numbered and registered to
record the exact size and dimensions of the pathologic
findings.
2.3 Histological assessment
The presence of BPH was recorded. The diagnosis
of prostate cancer was based on the criteria described in
the World Health Organization (WHO) classification
system [8]. Latent cancers were classified, by an expert
pathologist, according to the Gleason scoring system [9].
Cases of multi-focal tumors were classified according
to the prevalent histological model of the larger tumor
(index tumor). The diagnosis of AAH and the
discrimination between AAH and cancer were based on a
constellation of histological and cytological features [10, 11].
2.4 Classification
For statistical analysis purposes, AAH lesions were
divided according to the overall volume into small (< 0.5
mL) and large (> 0.5 mL). According to the grade of the
hypertrophy (BPH), prostates were studied in three
distinct groups (large > 50 mL, medium 25_50 mL and small
< 25 mL), and histological LPC were divided according to
overall volume into small (< 1mL) and large
(> 1mL).
2.5 Statistical analyses
The associations among AAH, BPH and LPC were assessed with paired
t-test and Mann_Whitney U-test.
3 Results
According to our findings, histological BPH was the
most common in our study population, accounting for
65.5% of prostates. Both AAH and LPC seemed less frequent, accounting for 15.5% (33 cases) and 18.8%
(40 cases), respectively.
Age specific prevalence of BPH was similar to that
of LPC but not identical: major prevalence of both
diseases was observed in men of the eighth and ninth
decade but BPH began to manifest in the male population
earlier. Major prevalence of AAH was observed in men
of the seventh and eighth decade (Table 1).
A possible relation between BPH, LCP and AAH has
been identified: both AAH and LPC were found more in
enlarged prostates than in small ones (< 25 mL). More
precisely, almost 22% and 29% of the prostates with
volume larger than 50 mL carried foci of AAH and LPC,
respectively (Table 2). However, since benign
hypertrophy existed in a greater percentage in specimens of all age
groups examined without LPC and AAH, no statistical
significant cross-correlation between BPH and LPC was
obtained (P > 0.05, Mann_Whitney
U-test). Interestingly, AAH and BPH were associated with larger prostate
volume (statistical significant cross-correlation among
BPH, AAH and prostate volume, P < 0.01).
Of the 40 LPC cases, 29 (72.5%) had an overall volume of less than 1 mL (average volume per focus less
than 0.5 mL), whereas almost all AAH lesions (29 cases,
[87.8%]) had an overall volume less than 0.5 mL. The
small AAH lesions showed an increased frequency in
enlarged prostates. Most LPCs of low volume showed
an increased frequency in medium-sized prostates
(Table 3). Parametric and non-parametric analysis did not confirm
any statistically significant relation between the
degree of BPH and the volume of latent carcinomas
(P > 0.05). Similarly, no associations were obtained regarding the
degree of BPH and the size of AAH lesions.
When presented with LPC (9 cases), AAH was found
with rather small sized LPC (especially in younger
subjects, Table 4), however, no statistically significant
correlation was obtained between AAH and overall
tumor volume (P > 0.05). No statistically significant
correlation (P > 0.05) was obtained between AAH and
histological differentiation of the concomitant tumors as well.
Similarly, no statistical significant cross-correlation was
found between BPH and histological differentiation of
the coexistent LPC (t-test, P = 0.907; Mann-Whitney
U-test 0.770).
Of cases of LPC, 87.5% (35 cases) were found to
originate from the peripheral zone (PZ) and only 12.5%
were found in the transition zone (TZ), where BPH also
develops. In contrast, almost all AAH lesions were
centrally located in the transition zone (TZ) or in the bound
between TZ and PZ. Although some AAH foci, especially those found on the boundaries between the
transitional and the peripheral zone, had similar appearance
with the well-differentiated LPC of TZ, no topographic
relationship between AAH and prostate carcinoma of the
TZ was found. Moreover, TZ and PZ LPC were nearly
equivalent when compared for histological
differentiation and tumor volume, respectively.
4 Discussion
AAH is a localized proliferative lesion whose occurrence, biological significance, pathogenesis and
aetiopathological association with other prostatic
conditions are controversial. AAH lesions consist of compact
clusters of uniform small glands [1, 12]. Nuclei are
slightly enlarged, the basal cell layer is often inconspicuous,
and the nucleoli are commonly small [12]. Although
reported in at least 20% of transurethral resection of the
prostatic gland specimens [13], its occurrence in the
general population is unknown. Differences in AAH
frequency between necropsy (15.5%) and surgery material,
could be explained by the relatively higher prevalence of
AAH in age groups 3 and 4 (Table 1), who actually
undergo surgery for BPH-related conditions. Moreover, as
the age of observed peak-incidence of AAH is similar to
that of BPH [14], differences in the overall prevalence of
AAH worldwide could be related to the differences in
BPH epidemiology [15]. Since the initial description of
AAH by McNeal [16] in 1965, its biological significance
remains controversial. AAH shares some common morphological characteristics with low-grade prostate cancer;
therefore, the distinction between the two entities is
often troublesome. Moreover, because Gleason pattern 1
and 2 carcinomas can sometimes closely resemble the
appearance of AAH, AAH might be, like high-grade
prostatic intraepithelial neoplasia, another precursor of
prostate cancer [17]. In the present study, the age-specific
prevalence of AAH showed a relative reduction after
70_79 years (age group 3), in contrast to the age-specific
prevalence of both LPC and BPH (which actually sustained their increasing rates), a finding which could
indicate that a percentage of AAH lesions in some patients
could have probably been transformed in other
lesions/entites (atrophy, neoplasm or otherwise) or gradually
degenerated. Furthermore, there are several similarities
between AAH and prostate cancer: AAH lesions are often
multi-focal, as is LPC, they display
high-density architectural arrangement and contain prominent nucleoli and
slightly enlarged nuclei. Several reports showed an
increased incidence of prostate cancer in the presence
of AAH [18]; according to Kastendieck, foci of atypical
primary hyperplasia are commonly found with low volume
high differentiated carcinomas [19]. Moreover, AAH
lesions have been reported to be in close proximity to
cancer lesions [13, 20]. In contrast, according to our
findings, AAH was equally distributed in both samples
with and without histological cancer, whereas, similarly
to other reports, no topographic relationship between AAH
and prostate carcinoma has been demostrated [20].
Beyond the topographic relationships, the aetiopathological
associations of AAH with other prostatic conditions are
controversial. The fact that AAH arises always in
prostates with concomitant BPH and exhibits several
cancer-like features, places AAH as an intermediate lesion
between BPH and the subset of well-differentiated cancers
in a hypothetical pathway between BPH and LPC: according to Bostwick
et al. [21], AAH could be related to the well-differentiated prostate cancers that arise in the
transitional zone in combination with BPH. In addition
to the numerical and topographical observations linking
AAH with BPH, rather than with small-volume
well-differentiated carcinomas, morphologic and histological
features of cancers that arise from the TZ (which contain
BPH nodules and AAH foci) and features of cancers that
arise from the PZ, showed no significant differences in
the present study [22]. Other studies provide further
evidence that AAH is histologically closer to BPH: the
AAH cell proliferation index was similar to those of BPH
[23], nuclear volume was closer to the volume observed
in BPH [19] and AAH cells had a normal DNA content
similar to the BPH cells [25_27].
According to the results from the present study, there
seems to be no causative aetiopathogenetical or
topographical relation between AAH lesions and prostate
adenocarcinoma. Although well-differentiated low
volume carcinomas of the TZ have been previously
correlated with AAH lesions, we did not observe such a
relation in our relatively small sample of TZ
carcinomas (12.5%). Despite the several morphological
characteristics of AAH suggesting a relationship with prostate
cancer, cellular changes observed in AAH are not
necessarily an element of malignant transformation, while
confounding atypical cellular features are occasionally seen
in confirmed benign lesions [28]. In conclusion, we
confirm that the AAH lesion is a well defined mimicker
of prostatic adenocarcinoma, whereas the reported
association of AAH with carcinoma is probably an
epiphenomenon. In addition, it seems that from the
perspective of the practicing urologist, currently, there is
no enough evidence to support the validity of a repeated
biopsy protocol in patients with AAH lesions, although
further studies are required to assess the need for such
recommendations.
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