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

Abstracts
second only to lung cancer. In recent decades we witnessed major advancements
in the understanding of the epidemiology, pathology and
pathogenesis of gastric cancer. Infection with H. pylori or Epstein-Barr
virus, dietary and lifestyle factors contribute to the risk of developing
gastric cancer. With regard to pathogenesis, at least three distinct types
of gastric cancer exist, i.e. (1) proximal, (2) distal diffuse, and (3) distal
non-diffuse type. Genetic and epigenetic alterations are related to oncogene
mutations and tumor suppressor gene inactivations, e.g. by loss
of heterozygosity or methylation. Canonical oncogenic pathways such
as E2F, KRAS, p53, and WNT/β-catenin signaling are de-regulated in
gastric cancer. Microsatellite instability is observed in approximately
10–15% of the cases. Hereditary and familial type gastric cancers are currently
linked to 122 different CDH1-mutations (25–30% of the cases with
Hereditary Diffuse Gastric Cancer) and various gene polymorphisms
determining disease susceptibility. Molecular subtypes of gastric cancer
were identified, which separate diffuse from intestinal type gastric cancer
and are not entirely congruent with the histopathological phenotype
according to Laurén, but may influence chemosensitivity. Putative cancer
stem cell markers of gastric cancer were found (e.g. ADAM17, CD133,
FZD7, LGR5), and correlate with patient prognosis. Perioperative chemotherapy
has improved patient survival and targeted therapy is applied
in patients overexpressing Her2/neu. With regard to patient prognosis,
complete surgical resection is still the most important predictor of patient
outcome, followed by tumor stage, lymph node ratio, and mucin
phenotype (Muc2). Among the diverse anxillary biomarkers that have
been sought and identified, including class I histone deacetylases, none
has reached a broader clinical application. Thus, molecular phenotyping
of gastric cancer is still in its infancies and the search continues for novel
diagnostic, prognostic and predictive biomarkers.
Keynote Lecture
VO-027
Mechanisms of androgen resistance in prostate cancer
D .J . Tindall1 1Department of Urology, Mayo Clinic Foundation, Rochester, United States
The androgen receptor (AR) signaling axis plays a critical role in the development,
function and homeostasis of the prostate. The classical action
of AR is to regulate gene transcriptional processes via AR nuclear
translocation, binding to androgen response elements on target genes
and recruitment of, or crosstalk with, transcription factors. Prostate cancer
initiation and progression is also uniquely dependent on AR. Androgen
deprivation therapy remains the standard of care for treatment of
advanced prostate cancer. Despite an initial favorable response, almost
all patients invariably progress to a more aggressive, castrate-resistant
phenotype. Considerable evidence now supports the concept that development
of castrate-resistant prostate cancer (CRPC) is causally related
to continued transactivation of AR. Understanding the critical events
and complexities of AR signaling in the progression to CRPC is essential
in developing successful future therapies. This talk provides a synopsis
of AR structure and signaling in prostate cancer in progression, with a
special focus on recent findings on the role of AR in CRPC. Clinical implications
of these findings and potential directions for future research
are also outlined.
12 | Der Pathologe · Supplement 1 · 2012
Pankreaskarzinom
VO-029
Molecular alterations in pancreatic ductal adenocarcinoma
B . Sipos1 1University of Tübingen, Department of Pathology, Tübingen
In the last decade significant results have been achieved in understanding
the molecular pathogenesis of pancreatic ductal adenocarcinoma
(PDAC). Holistic approaches searching for genetic abnormalities indicate
that PDACs harbor one or more genetic alterations in the majority
of core pathways. These pathways include apoptosis, DNA damage and
G1-S phase transition control; homophilic cell adhesion and integrin
signaling; c-Jun, K-ras and other small GTPases associated pathways;
TGF-beta, hedgehog and Wnt/notch signalling and finally the regulation
of invasion. In the initiation of human PDACs K-ras, p53, DPC4/
Smad4 and p16/CDKN2a play a pivotal role, which is demonstrated by
the increasing rate of alterations of these genes during progression of
pancreatic intraepithelial neoplasia.
Beyond these descriptive data from human studies on pancreatic intraepithelial
neoplasia, experiments using genetically engineered mouse
models (GEMM) provide functional evidence that K-ras, p53, p16/
CDKN2a alterations are key factors in emerging PDACs. GEMM that
express mutant oncogenes and/or tumor suppressor genes under the
control of pancreas specific promoters such as elastase, Pdx-1 and p48/
Ptf1a recapitulate the progression of pancreatic intraepithelial neoplasia
to PDAC, following a characteristic acinar-ductal metaplasia in the pancreatic
parenchyma. These GEMM give rise to PDAC, but also to other
types of cancer. Targeting K-ras and p53 in GEMM results in well-reproducible
tumor development, which allows reliable pre-clinical in vivo
experiments in conjunction with sophisticated small animal imaging.
High stroma content and paucity of intratumoral vessels are hallmarks
of human PDAC. The stroma contains stellate cells, immune cells and
large amounts of extracellular matrix, which all contribute to the malignant
traits of PDACs and may even exert a selective pressure on tumor
cells. Desmoplasia probably contributes to the innate chemoresistance of
PDACs by hindering drug delivery.
To date, there is no efficient targeted therapeutics for human PDAC. Targeted
treatment may fail due to numerous affected pathways that facilitate
evasion of tumor cells from the pressure of selective blocking agents.
In the next decade the big challenge is to find the Achilles’ heel of PDAC,
probably using intelligent combination of smart molecules and targeting
of the stroma.
VO-030
The CRM concept of pancreatic cancer – a proposal for the new
S3-Guideline
A . Tannapfel1 1Institut für Pathologie, Bochum
Pancreatic ductal adenocarcinoma is diagnosed in about 13,000 patients
each year in Germany being the fourth leading cause of cancer mortality.
The 5-year survival rate remains less than 5% because of metastatic disease
at time of initial diagnosis. It becomes evident, that ductal pancreatic
cancer develops in a sequential process from lesions, named as Pancreatic
Intraepithelial Neoplasia (PanIn). The curative removal of the tumor
(R0 resection) may improve survival, but survival remains poor even in
optimally resected patients. Loco regional and metastatic recurrence is
frequent. The rate of microscopic margin involvement (R1) varies markedly
in the current literature (from 5 to 85%). The rate of R1 resections
is frequently underreported. One possible reason is the lack of the uniform
use of R classification, followed by the lack of quality assessment
for pathological examination of pancreaticoduodenectomy specimens.
A standardized protocol for pathological examination should be used