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

Abstracts
VO-017
Translational research and diagnostics – GIST
E . Wardelmann 1
1 University of Cologne, Institute of Pathology, Köln
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal
tumors in the digestive tract. In up to 90% of cases, they are
characterized by activating mutations in the KIT or the PDGFRA gene.
GIST turn out to be a paradigm for successful targeted treatment with
tyrosine kinase inhibitors (TKI). Since the approval of the TKI imatinib
in 2002 the survival of patients with metastatic GIST has been tripled.
The next logical step was the concept to use imatinib in an adjuvant
approach which recently showed to increase the overall survival significantly.
In both settings, the mutational status has high predictive implications.
In detail, GIST with KIT exon 11 mutations show the best response
rates with partial remission rates of up to 80%. In KIT exon 9 mutations,
a doubled daily dose of 800 mg imatinib is now the standard. The
PDGFRA exon 18 mutation D842V has been shown to lead to a primary
resistance. Conclusively, the treatment strategy in GIST is driven by their
molecular characterisation.
Further research has increased the knowledge about resistance mechanisms
in solid tumors against TKI. The number of patients with secondary
resistance due to acquired KIT mutations is increasing with treatment
duration. Strategies to address this situation are the introduction of
novel pathway inhibitors targeting different levels of signal transduction
pathways such as the mTOR/Akt pathway, the RAS/RAF pathway, histone
deacetylation, and others.
Among the GIST without mutations in the common hot spot regions
of KIT and PDGFRA, so-called wild type GIST, further genomic subgroups
have been identified. One such subgroup carries inactivating
germline mutations in the genes encoding succinate dehydrogenase B,
C, or D. They are associated with the occurrence of paragangliomas, the
so-called Carney-Stratakis syndrome. Most frequently, GIST are located
in the stomach and show an epithelioid phenotype and a multinodular
growth pattern. They preferentially occur in young females and often
show lymph node metastases. In Carney’s triad additional pulmonary
chondromas are observed. Another small subgroup of sporadic GIST
present with BRAF mutations as an alternative genomic event. Finally,
very rare kindreds with germline mutations in either KIT or PDGFRA
have been described.
In summary, the molecular characterisation of GIST has revolutionized
their treatment because of increasing knowledge about the high relevance
of predictive molecular typing in solid tumors.
Translationale Forschung und Diagnostik –
Niere, abl. Harnwege, Prostata
VO-018
Biomarker for diagnosis, prognosis and prediction in renal cancer
H . Moch1 1University Zurich, Institute for Pathology, Zürich, Switzerland
Biomarkers are frequently used in aiding diagnosis, and to predict prognosis
or response to therapy in neoplasms. In renal cancer, immunohistochemistry
is commonly used in the routine for the classification of
renal tumors. Conventional karyotyping, fluorescence in situ hybridization
and molecular cytogenetics are less commonly used. Expression
profiling, and mutational analysis are currently performed to identify
specific molecular pathways in renal cancer, mainly for research purposes.
In this presentation, we document results of a Working Group Meeting
conducted by the International Society of Urological Pathology (ISUP) in
10 | Der Pathologe · Supplement 1 · 2012
Vancouver 2012. The Working Group discussed the use of immunohistochemical
markers as well as the use of cytogenetics or other molecular
technologies in the characterization of renal neoplasms. In this presentation,
the results of the Working Group Meeting are summarized. In
detail, the value of immunohistochemistry for the differential diagnosis
in different diagnostic situations, e.g. in renal tumors with clear or granular
cytoplasm, diagnosis of unclassified renal cancer is commented.
Further, the view of the Working Group regarding use of predictive or
prognostic biomarkers in routine pathology is provided.
VO-019
Translational research and diagnostics: urinary tract
R . Knüchel-Clarke1 , N .T . Gaisa2 , M . Rose2 , C . Henkel3 , E . Dahl2 1 2 Universitätsklinikum Aachen, Institut für Pathologie, Aachen, University
Hospital, RWTH Aachen, Institut für Pathologie, Aachen, 3Ruhr-University Bochum, Medical Proteomics Center, Bochum
In urothelial cancer as a frequent tumor entity two main fields of the
clinical situation deserve special attention and need support from basic
research.
1. Amongst the most frequent non-invasive papillary low grade tumors
morphology alone is insufficient to predict recurrence rate or even more
importantly progression.
2. Amongst the already muscle invasive tumors which mostly undergo
cystectomy, neoadjuvant and adjuvant chemotherapy concepts still have
a limited supportive role, and more effective individualized treatment
concepts are desirable.
Ad 1. While the WHO classification of tumors has integrated data from
genetic analysis of tumors to diagnose genetically stable (low grade) and
unstable (high grade) tumors, FGFR3 mutations and additional molecular
alterations may help to define the non-progressing, i.e. nearly benign
tumors within the group of low grade tumors. This could support therapy
decision favoring avoidance of intravesical chemotherapy and allowing
less follow up. A multiparametric approach will be necessary and
becomes increasingly feasible due to e.g. epigenetic or proteomic marker
sets. Ideally these marker sets are not only valid for tissue analysis but
also sufficiently sensitive to predict benign disease course in cytology
specimens.
Ad 2. Within the group of genetically instable tumors it seems necessary
to define tumors different from mere urothelial differentiation as
squamous and glandular as well as variants of urothelial carcinoma as
micropapillary or small cell carcinoma in a first step. All these tumor
variants are found in other organs as well. Consequently the multicentric
collection of cases and the molecular analysis of pathways of growth
signalling is an apt approach for target identification. Data should be
compared to already established data in other cancers as colon and lung
cancer and will allow the inclusion of cases in prospective studies using
e.g. small molecule- like tyrosine kinase inhibitors. Own research efforts
and recent data from the literature that intend to improve the two clinical
settings in urothelial cancer will be presented.
With support of a START grant RWTH Aachen (MR, NTG and ED) and
a DFG grant GA 1384/2-1 (NTG).
VO-020
Translational research and diagnosis of prostate cancer
G . Kristiansen1 1Institut für Pathologie der Universitätsklinik Bonn, Bonn
Prostate cancer is the most common non-cutaneous malignant tumour
in men and is a major research focus of pathologists, urologists and urooncologists
alike. Due to PSA-screening and risen patient awareness, the
practising pathologist is confronted with a steadily increasing number of
prostate biopsies, necessitating ancillary tests in morphologically challenging
cases. Next to basal cell markers, additional positive markers