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RES E AR C H Open Access
Increased expression of α-methylacyl-coenzyme A
racemase (AMACR; p504s) and p16 in distal
hyperplastic polyps
Nimet Dayi
1
, Hideo A Baba
2
, Kurt W Schmid
2
and Klaus J Schmitz
2,3*
Abstract
Background: Hyperplastic polyps (HP) and sessile serrated adenomas (SSA) share morphological similarities. In this
immunohistochemical study we chose a panel of potential relevant and promising biomarkers including
α-methylacyl-coenzyme A racemase (AMACR; p504s), which is involved in the degradation of branched chained
fatty acids derivates, and analysed a cohort of HPs and SSAs in order to identify different immunophenotypes in
relation to lesion localisation.
Methods: 154 specimen were carefully selected and a micro tissue array (TMA) was constructed.
Immunohistochemistry of p16
Ink4a
, Ki67, α-methylacyl-coenzyme A racemase (AMACR; p504s), BRAF, CK 20, MLH1
and β-catenin was performed and and immunoexpression was compared among proximal and distal HPs as well as
SSAs.
Results: Non e of the markers revealed a differential expression among HPs and SSAs. Ho wever, the study
demonstrates a significant overexpression of AMACR (p = 0.004) and p16
Ink4a
(p = 0.028) in distal HPs compared
to proximal HPs. In addition AMACR overexpression was associated with increased p16
Ink4a
immunoexpression
(p < 0.001).
Conclusions: In this study we describe differential AMACR and p16
Ink4a
in HPs in relation to their local isation.
Distal HPs were characterized by AMACR and p16
Ink4a
overexpression in contrast to proximal HPs, although
morphological identically. Thus AMACR overexpression points towards a pathobiological relevance of the
proteinindistalHPs.Incontextofrecently pub lished data this suggest distal HPs a s potential precursor lesions
of certain adenoma subtypes. However, at this point of time this finding remains speculative and needs to be
confirmed by further studies.
Virtual slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.
eu/vs/1836116001066768
Keywords: AMACR, p16
Ink4a
, Hyperplastic polyp, Sessile serrated adenoma
Background
Historically hyperplastic polyps have been considered
benign and harmless lesions for several decades [1]. Mean-
while it is known, that besides of the classical adenoma-
adenocarcinoma path way described by Vogelstein [2],
an additional (non-hereditary) pathways exist s , called
the serrated pathway [1,3-6] resulting in serrated lesions
such as the sessile serrated adenoma (SSA) and serrated
adenocacinoma. The serrated morphology of this pathway
reflects the disorder in impaired apoptosis resulting in
retention of epithelial cells at the base of the crypts.
Molecular key features of the classical adenoma-
adenocarcinoma include KRAS and p53, whereas in the
serrated pathway BRAF mutations appear to be an early
event [2,7-9]. In addition this initial event is often followed
by hypermethylation of CpG-island in gen promoters. As
a result of hypermethylation e.g. MLH1 genes are silenced
* Correspondence: kjschmitz@p athologie-re.de
2
Institute of Pathology and Neuropathology, University of Duisburg-Essen,
Hufelandstrasse 55, 45122 Essen, Germany
3
Institute of Pathology Recklinghausen, Mühlenstrasse 31, 45659
Recklinghausen, Germany
Full list of author information is available at the end of the article
© 2013 Dayi et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Dayi et al. Diagnostic Pathology 2013, 8:178
http://www.diagnosticpathology.org/content/8/1/178
resulting in the well known and characteristic (sporadic)
microsatellite instable phenotype and genotype, which
often occurs in SSA and serrated adenocarcinoma [10].
Meanwhile several pathomorphogical criteria have been
established, that allow a stricter separation of SSAs and
hyperplastic polyps (HPs) [3,11]. However, clear separation
of SSA and HP in individual cases is sometimes impos-
sible. In addition, even HPs may harbour somatic BRAF
mutations and an so-called CPG island methylator pheno-
type (CIMP) [12,13]. Thus a subset of HPs may be precur-
sor lesions of SSAs.
The aim of this study was to analyse several immunohis-
tochemical markers in order to 1) identify additional
markers, that may allow a more clearly separation of HPs
and SSAs and 2) to compare proximal and distal HPs and
to work out potential different immunophenotypes of
proximal versus distal HPs.
The antibodies used in this study were the following:
1) p16
Ink4a
, which is an important factor in carcinogen-
esis and wa s shown to be linked to oncogene-induced
senescence in the serrated route to colon cancer [14];
2) Ki67, which represents a established proliferation
marker; 3) α-methylacyl-coenzyme A racemase (AMACR;
p504s). AMACR is a mitochondrial and peroxisomal en-
zyme that is part of the degradation of branched chained
fatty acid derivates. AM ACR is essential for the comple-
tion of the β-oxidation pathway [15] a nd ha s re cently
been shown to upregulated in colorectal cancer and
adenoma [16-18]; 4) B RAF, MLH1 and β-catenin as
addit ional markers involved in the serrated adenocarcin-
oma carcinogenesis.
Material and methods
Specimen
Initially 891 biopsy specimen from 2009 to 2012 re-
presenting HPs and SSAs were retrieved from the files of
the Institute of Pathology, Recklinghausen. The slides of
these specimen were re-evaluated by the authors KJS and
ND. All biopsies, that did not allow optimal evaluation of
the complete lamina propria (including the base of the
crypts) were excluded from further investigation (n = 737).
In the remaining 154 specimen, lesion localisation was de-
fined as proximal, if retrieved from coecum or ascending
colon. Distal localization included specimen derived from
descending colon, sigmoid or rectum. Table 1 depicts rele-
vant clinical data of the study group.
Tissuemicroarray (TMA) construction
SSA and HP areas were carefully selected and marked
on the respective H&E (haematoxylin and eosin-stained)
slides. TMA construction was performed as previously
described [19]. The TMA included 154 specimen.
Immunohistochemistry of TMA
The primary antibodies used as well as the technical
details are summarized in Table 2.
Evaluation of immunohistochemistry
AMACR: AMACR expression was scored according to
the intensity of solely basal crypt cytoplasmic staining pat-
tern. AMACR negative (0): no basal staining; AMACR
positive (1+): cytoplasmic immunostaining of basal located
crypt epithelial cells, independent of the intensity.
P16: p16 expression was scored according to the inten-
sity of solely basal crypt nuclear and cytoplasmic staining
patterns. p16 negative: missing basal immunostaining; p16
positive: basal positive nuclear and cytoplasmic staining.
Ki67: Ki67 expression was scored according to the posi-
tivity of epithelial cells in the upper third of the crypts.
Positive cells were counted.
Cytokeratin 20: all cases showed an upper crypt stain-
ing and scattered basal stained cells. Cases were scored
according the Cytokeratin 20 staining pattern: usual pat-
tern (staining confined to uppe r crypt zone) and unusual
pattern (additional scattered positivity in the basal crypt
zone).
BRAF, MLH1 and β-cat enin: MLH1 immunostaining
revealed no morphological differences among different
groups (HP versus SSA) or different localizations (prox-
imal vs. distal). A weak MLH1 staining was noticed in
all specimen. BRAF immunostaining was weak to nega-
tive in all cases (although external control specimen
containing BRAF mutations resulted in positive immu-
nostaining). β-catenin immunostaining resulted in strong
cytoplasmic and nuclear staining of the complete basal
crypt zone of all specimen. BRAF, MLH1 and β-catenin
were excluded from further analysis.
Statistical analysis
All immunostainings were assessed by KJS and ND in a
blind trial fashion. In ca se of disagreement, slides were
re-evaluated by both investigators until agreement wa s
reached. All data were converted to a PC and statisti-
cally analysed using SPSS ve rsion 20 for Macintosh
(Statistical Package for Social Sciences, Chicago, IL, USA).
Relationships between ordinal parameters were investi-
gated using the two-tailed χ
2
analysis. The relationship be-
tween categorical data (e.g. SSA versus HP) and numeric
Table 1 Clinical details of the study group
Variables Results
Proximal HPs Distal HPs SSAs
Gender
Male 21 39 18
Female 27 28 14
Mean age in years 65.45 62.70 65.35
Dayi et al. Diagnostic Pathology 2013, 8:178 Page 2 of 6
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data (number of Ki67 positive cells) was determined using
the Kruskal Wallis test.
Results
Table 3 summarizes the amount of specimen included
in this study and analysed for A M ACR and p16
immunoexpression.
AMACR immunostaining was located in the cytoplasm
of upper and basal crypt cells. Only basal location was
analysed. Regarding the group of HPs, χ
2
analysis showed,
that distal HPs exhibited statistically significantly positive
AMACR expression (p < 0.004; Table 4). Figure 1 demon-
strates AMACR expression in SSA and HP.
Regarding the group of SSA, no statistically different
AMACR immunoexpression could be detected among
proximal and distal SSAs (p = 0.329). In addit ion a com-
parison of all SSAs versus all HPs revealed no differ-
ences in AMACR expression (p = 0.448).
P16 immunostaining was located at the basal crypt zone
in the cytoplasm and nucleus of crypt cells (Figure 2). If
all HPs were compared to all SSAs no statistical difference
in p16 expression was detected (p = 0.183). The analysis of
proximal versus distal HPs demonstrated a significantly
stronger p16 immunoexpression in distal HPs (p = 0.028;
Table 4).
Further we analysed the association of AMACR and
p16 expression within the group of HPs. There was a
highly significant association of AMACR overexpression
with p16 positivity in HPs (p < 0.001; Table 5).
Ki67: Ki67 analysis of HPs versus SSAs and within the
groups of HPs or SSAs revealed no significant results.
There were no statistically significant differences between
the mean Ki67 value in HPs versus SSAs. However the
mean value of KI67 proliferating cells was higher in SSA
compared to HP.
Cytokeratin 20: Cytokeratin 20 analysis of HPs versus
SSAs and within the groups of HPs or SSAs revealed not
significant results. There were no differences in the
distribution of CK20 staining of the upper crypt zone
and the basal zone.
MLH1: MLH1 analysis of HPs versus SSAs and within
the groups of HPs or SSAs revealed not significant results.
TherewerenodifferencesinthedistributionofMLH1
staining of the upper crypt zone and the basal zone.
Beta-catenin: analysis of HPs versus SSAs and within
the groups of HPs or SSAs revealed not significant results.
All cases revealed a cytoplasmic/nuclear staining at the
basal crypt zone.
BRAF: All cases revealed a weak to negative staining
without significant differences. All cases lacked positive
staining results, altho ugh HPs frequently demonstrate
BRAF mutations and despite of positive external study
controls. Thus BRAF immunohistochemistry in this study
is not a reliable tool to detect BRAF mutations in HPs or
SSAs.
Discussion
This study on a cohort of HPs and SSAs demonstrates,
that HPs exhibit different immunophenotypes regarding
to their localization (proximal vs. distal). The Immuno-
histochemical analysis included the following markers:
AMACR, p16
Ink
, CK20, Ki67, BRAF, β-catenin and
MLH1. We focussed on the expression of AMACR and
p16
Ink
in HPs and SSAs with respect on lesion localisa-
tion since analysis of CK20, Ki67, BRAF, β-catenin and
MLH1 either lacked significant results or resulted in
Table 2 Antibodies used for immunohistochemistry
Antibody Pretreatment Incubation Detection Dilution Company
AMACR Monoclonal 98°C Hot
water, pH 9.0,
15 min Envision™ Ready-to-Use Kit Dako, Glostrup, Denmark
p16Ink Monoclonal,
clone G175-405
98°C Hot
water, pH 6.1,
20 min Envision™ 1:10 BD Biosciences,
Heidelberg, Germany
Ki67 Monclonal, clone
MIB-1
98°C Hot
water, pH 9.0,
15 min Envision™ Ready-to-Use Kit Dako, Glostrup, Denmark
BRAF Monoclonal,
clone VE1
37°C Hot
water, PH 9.0
30 min Envision™ 1:100 DCS Innovative Diagnostik,
Hamburg, Germany
MLH1 Monoclonal,
clone ES05
98°C, pH 9.0 20 min Envision™ Ready-to-Use Kit Dako, Glostrup, Denmark
Beta-catenin Monoclonal 37°C water
bath 30 min
20 min Zytochem Plus HRP Polymer
(Zytomed Systems, Berlin, Germany)
1:2000 BD Biosciences, Heidelberg,
Germany
CK20 Monoclonal,
Clone Ks20.8
98°C, pH 9.0 30 min Envision™ Ready-to-Use Kit Dako, Glostrup, Denmark
Table 3 Specimen analysed for AMACR and p16
immunoexpression
AMACR N Localization p16 N Localization
106 Distal Proximal 109 Distal Proximal
HPs 82 49 33 HPs 83 50 33
SSAs 24 11 13 SSAs 26 12 14
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unreliable data. All parameters analysed are involved in
the serrated adenocarcinoma pathway. Besides the well
known AMACR overexpression in prostate cancer [20],
overexpression was also demonstrated in colorectal can-
cer [21]. Moreover dyspla stic epithelial cells in Barrett
Oesophagus were shown to be associated with elevated
AMACR levels [22].
Likewise SSA s, HPs have been shown to harbour spe-
cific genetic alterations such as somatic BRAF mutations
and CPG island methylator phenotype (CIMP) [12,13].
This suggest s the progression of a subset of HPs towards
SSAs. Thus one of our study aims was to identify poten-
tial biomarkers , that may allow more precise separation
of HPs and SSAs and identify a subset of HPs that might
qualify as precursor lesions of SSAs. However, the
analysed biomarkers did not provide additional diagnos-
tic information allowing a more distinct differentiation
of HPs and SSAs. Recently Ki67 counting and distribu-
tion was shown to be different in HPs versus SSAs, with
higher Ki67 values in SSAs [23]. However, in our study
we could not confirm this finding. This might be due to
the fact, that in our study only a small number of SSAs
were analysed. In addition in the study by Fujiimori
et al. Ki67 evaluation was calculated using automated
image proce ssing software, whereas this was not the case
in the present study.
Furthermore this study describes a significant over-
expression of AMACR in left-sided distal HPs whe n
compared to right-sided proximal HPs. Thus although
morphological identically these lesions exhibit a varying
AMACR immunophenotype. It is unlikely, that these
distal HPs are at higher risk to progress to SSAs , since
SSAs are typically located proximal in the right colon.
Given the known func tion of A MACR regarding fat me-
tabolism, it may be possible, that in the distal parts of
the colon the mucosa is exposed to an increased amount
of branched-chain fatty acids and fatty acid derivates.
Another possible explanation would be a specific
supportive role of A M ACR in the development of pre-
cursor lesions in the colore ctal cancer carcinogenesis.
This hypothesis is supported by re cent data demon-
strating increa sed AM ACR expression in high grade
dysplasia compared to low grade dysplasia in conven-
tional adenomas [18].
Until now only few studies focussed on AM ACR ex-
pression in ga strointestinal tumours. In a recent study
Table 4 AMACR and p16 expression in proximal and distal HPs
AMACR (n = 82) p16 (n = 83)
Negative Positive p-value Negative Positive p-value
Proximal HPs 28 (84,8%) 5 (15,2%) 0,004 31 (96,6%) 1 (3,1%) 0,028
Distal HPs 27 (55,1%) 22 (44,9%) 41 (80,4%) 10 (19,6%)
Figure 1 On the left HP with strong basal AMACR immunoexpression. On the right higher magnification of cytoplasmic granular AMACR
expression at the base of the typically L-shaped, dilated SSA crypts (magnification × 400).
Dayi et al. Diagnostic Pathology 2013, 8:178 Page 4 of 6
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on 1315 colorectal cancers AM ACR overexpression was
found to be associated with left-side tumour localisation
in colorectal cancer [16]. In detail, A M ACR elevation
was significantly associated with higher tumour differ-
entiation grade (G1 and G2) and advanced tumour
stage. In addition high AMACR expression levels were
related to a tubular phenotype and less often to mucin-
ous or signet cell carcinoma s. These results presented
by Marx et al. point towards a relevant role of AM ACR
expression at least in a subgroup of colore ctal cancer
and implicate a linkage of AM ACR expression and
site-related differences in metabolism/exposure to fatty
acids.
In the present study in addition to differential expres-
sion of AMACR in HPs, we were able to detect significant
differences in the expression of p16
Ink4
in proximal and
distal HPs. Similar to AMACR, p16
Ink4
was overexpressed
in distal HPs and significantly associated with AMACR
overexpression. p16
Ink4
is a well characterized protein with
an important role in oncogene-induced cell aging [24,25].
Upregulation of p16
Ink4a
was recently shown to function
as an senescence barrier in the serrated route to colon
cancer [14].
Taken together the overexpression of AMACR and
p16
Ink
in distal HPs points toward a pathophysiological
relevance of both these proteins. It is now necessary to
identify in which processes AMACR and p16
Ink
in distal
HPs are involved and if their dysregulation is implicated
in the development of certain subgroups of adenomas.
Highly interesting in this context is a very recent study
from Zhang et al. that analyses AMACR expression in
normal mucosa, adenoma and colorectal carcinoma both
on immunohistochemical and genetic level [17].
Zhang et al. reported AMACR negativity in normal co-
lonic mucosa and tubular adenoma with low grade and
intermediate dysplasia as well as in poorly differentiated
carcinoma. In contrast AMACR overexpression was found
in villous adenoma and high and moderately differentiated
colon cancer. These results are in concordance with those
of Marx et al. Using Laser-capture-microdissection Zhang
et al. discovered different deletions in the AMACR pro-
motor CpG Island, depending upon the underlying tissue:
In normal colonic glands and tubular adenomas with
low AMACR expression they detected a somatic double-
deletion at CG3 and CG10, that was absent in villous
adenomas and all colon cancers with variable AMACR
levels. In contrast they identified a high prevalence (89%)
of deletion of CG12-16 in moderately differentiated colon
cancers with strong AMACR overexpression, whereas
these deletions existed in only 14% of poorly differentiated
colon cancer. This deletion of CG12-16 was shown to be a
constitutional allele with a frequency of 43% in the general
population.
Taken together, AMACR protein expression may be reg-
ulated by somatic or constitutional genetic alterations in
AMACR Promoter CPG islands. Keeping the above men-
tioned findings in mind, it is now tempting to speculate,
that distal HPs with increased AMACR expression might
constitute precursor lesions of a pathway leading to the
Figure 2 On the left strong nuclear p16 expression in a distal hyperplastic polyp. On the right missing to low p16 expression in a proximal
HP (magnification × 200).
Table 5 Association of AMACR and p16 in HPs
HPs (n = 75) p16 immunoexpression
Negative Positive p-value
AMACR positive 49 (75%) 1 (9,1%) <0.001
AMACR negative 27 (25%) 10 (90,9%)
Dayi et al. Diagnostic Pathology 2013, 8:178 Page 5 of 6
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development of villous adenomas and/or subtypes of low
grade colorectal cancers.
Conclusions
This study demonstrates differential expression of AMACR
and p16 in morphologically similar looking HPs in relation
to their localisation. Distal located HPs exhibit AMACR
and p16 overexpression compared to proximal HPs. The
reasons and pathobiologically significance of this varying
immunophenotype needs be elucidated in further studies.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
ND and KJS drafted the manuscript, ND analysed Immunohistochemical data
and performed TMA construction and data collection. HAB and KWS
participated in the design of the study, have made substantial contributions
to conception and design as was data analysis and have given final approval
of the version to be published. KJS has performed statistical analysis. All
authors read and approved the final manuscript.
Author details
1
St. Barbara-Hospital, Barbarastrasse 1, 45964 Gladbeck, Germany.
2
Institute of
Pathology and Neuropathology, University of Duisburg-Essen, Hufelandstrasse
55, 45122 Essen, Germany.
3
Institute of Pathology Recklinghausen,
Mühlenstrasse 31, 45659 Recklinghausen, Germany.
Received: 9 September 2013 Accepted: 15 October 2013
Published: 23 October 2013
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Cite this article as: Dayi et al.: Increased expression of α-methylacyl-
coenzyme A racemase (AMACR; p504s) and p16 in distal hyperplastic
polyps. Diagnostic Pathology 2013 8:178.
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