96. Jahrestagung der Deutschen Gesellschaft für Pathologie e. V ...

within the earliest morphologic detectable alterations, i.e. clear cell foci
(CCF) of altered hepatocytes. CCF are described in humans indeed, but
it is unclear whether these proto-oncogenic pathways are already activated
within these foci.
Methods. 241 liver resections were examined by using electron microscopy,
histology, enzyme- and immunohistochemistry.
Results. CCF are present within 35% of the extrafocal tissues of non
cirrhotic livers. Electron microscopy illustrates massive glycogen storage
within CCF, largely due to reduced activity of the glycogenolytic
enzyme glucose-6-phosphatase. Hepatocytes of the CCF overexpress
the insulin receptor and the glucose transporter proteins GLUT1 and 4.
Insulin induced protooncogenic pathways AKT/mTOR (AKT, chREBP,
activated mTOR, inactivated AMPKalpha, activated RPS6, inactivated
4EBP1) and Ras/Raf1 (IRS1, Ras, Raf1, MEK-1, ERK1/2, MKP-3, RALA),
enzymes of glycolysis (Glucokinase, PFK, Pyruvate kinase), de novo lipogenesis
(ACLY, ACAC, FASN, USP2, AKR1B10, SCD1), beta-oxidation
(ACADM) and cholesterol synthesis (HMGCoAR, SQS) are upregulated
in the CCF compared to normal liver tissue. Due to activation of these
proto-oncogenic factors the proliferation activity in the CCF is 2-fold
higher than in extrafocal tissue (Ki67-Index 0.75% vs. 0.36%; p=0.002).
Conclusions. CCF reveal a phenotype which is known caused by hyperinsulinism
in experimental hepatocarcinogenesis models as well as in
human hepatocellular carcinomas. These metabolic changes and activation
of proto-oncogenic pathways have not been observed in human
CCF so far. Our results indicate that CCF represent precursor lesions of
hepatocellular carcinoma also in humans.
FR-P-111
Adjuvant fluorescent in situ hybridization in equivocal biliary and
pancreatic duct cytology
M . Schramm1 , A . Thieme1 , N . Pomjanski1 , H . Neuhaus 2 , A . Böcking1 ,
S . Biesterfeld1 1Heinrich Heine University, Institute of Pathology, Düsseldorf,
2Evangelical Hospital, Düsseldorf
Aims. The information whether a stricture or compression of the biliary
and pancreatic ducts is of benign or malignant nature is important
for therapy planning. Brushing of the suspect lesion in the context of
an endoscopic retrograde cholangiopancreaticography is an established
diagnostic procedure with moderate sensitivity and high specificity of
conventional cytological diagnosis. Equivocal cytology due to artefacts
or insufficient sampling is frequent. The detection of aneusomy by multicolour
fluorescent in situ hybridization (FISH) is strongly associated
with malignancy. The concern of our study was to determine if the addition
of FISH subsequent to the cytological investigation could substantially
decrease the number of equivocal cytology diagnoses.
Methods. A cohort of 235 biliary/pancreatic duct brushings sent to the
Department of Cytopathology during January 2005 and December
2007 was enrolled in this study to determine the diagnostic accuracy of
cytology. In a second series of 143 brushings, consisting of all positive
specimens (positive control) and all equivocal specimens in the above
mentioned period and negative specimens in the period from January
to December 2007 (negative control), aneusomy was analysed with the
UroVysion FISH multiprobe. A histological and/or clinical follow up
according to a reference standard, defined in advance had been available
for 219 brushings.
Results. In the whole cohort, cytology achieved a sensitivity and specificity
of 75.3% and 93.1%, respectively. The reduced specificity, compared
with the literature was attributable to the use of cytology as a screening
test; all equivocal specimens were assigned as positive for statistics. FISH
identified 29 out of 38 (76.3%) evaluable cytologically equivocal specimens
as true positive and 9 out of 9 (100%) as true negative, compared to
the follow up. All cytological negative (January to December 2007) and
28 out of 29 positive specimens were confirmed by FISH. Aneusomy was
not observed in benign lesions, according to follow up data.
Conclusions. Adjuvant analysis of aneusomy with multicolour FISH in
biliary/pancreatic duct brushings reduces equivocal cytology rate to a
great extent and is 100% specific.
Poster: Herz- und Gefäßpathologie
FR-P-112
The impact of genetic inactivation of the LIM-ony-protein FHL2
on cardiac remodelling
D . Goltz1 , E . Ramadori1 , S . Huss2 , M . Besmens3 , R . Meyer4 , R . Büttner2 1 2 University of Bonn, Dept . of Pathology, Bonn, University of Cologne, Dept .
of Pathology, Köln, 3University of Bonn, Physiology II, Bonn, 4University of
Bonn, Physiology II, Bonn
Aims. LIM-domain containing proteins play a decisive role during ontogenesis
and cellular differentiation. The LIM-only protein Fhl2 associates
with cytoplasmatic scaffolding proteins and acts intranuclearly as a
co-activator and co-repressor of transcription factors. Fhl2 is specifically
expressed within the cardiovascular system during ontogenesis and high
expression levels continue throughout lifetime. This suggests that Fhl2 is
also of importance during cardiovascular remodelling. Fhl2 deficiency
is known to induce an exacerbated cardiac hypertrophy upon chronic
beta- adrenergic stimulation. This study investigates cardiac remodelling
in the Fhl2 deficient organism caused by an increase in cardiac afterload.
Methods. Experimental transverse aortic constriction (TAC) was induced
in control animals and Fhl2-/- mice. After 14 days, morphometric
and hemodynamic evaluations using a Millar catheter were performed.
Vascular contraction and relaxation was examined using a Mulvany
myograph and renal renin-mRNA-expression was analysed by quantitative
real time PCR. Cardiac fibrosis was addressed by histologic techniques.
Results. TAC induced a rise in pre-stenotic diastolic arterial blood pressure
and a significantly more severe increase in pre-stenotic systolic arterial
blood pressure in the Fhl2-/- animal compared to the control animal.
The transstenotic pressure gradient, however, was identical in the Fhl2-
/- animal and the control animal. In vitro vascular contraction measurements
proved that aortic rings of Fhl2 deficient mice featured combined
contractile dysfunction and disturbed relaxation that was independent
of receptor mediation. As a consequence, renal renin-mRNA-expression
was significantly suppressed in Fhl2-/- mice. Cardiac hypertrophy, however,
was less distinct in Fhl2 deficient animals than in wild type animals
as was cardiac fibrosis.
Conclusions. Fhl2 deficiency encompasses cardiac protection against
chronic increases in cardiac afterload, in this context due to a suppression
of the renin angiotensin axis.
FR-P-113
The impact of Crp2 deficiency on cardiovascular adaptation and
remodelling
D . Goltz1 , E . Ramadori1 , S . Huss2 , R . Meyer3 , R . Büttner2 1 2 University of Bonn, Dept . of Pathology, Bonn, University of Cologne, Dept .
of Pathology, Köln, 3University of Bonn, Physiology II, Bonn
Aims. Lim domain containing proteins among them Crp2 play a central
role in organogenesis and cellular differentiation. Crp2 is specifically
expressed in cardiovascular tissue. Its up-regulation in cardiomyocytes
coincides with vascular smooth muscle differentiation in vitro. We investigated
the vascular phenotype of Crp2 deficient mice in vitro and
addressed the issue of cardiac remodelling under chronic elevation of left
ventricular afterload in vivo.
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