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

Abstracts
DO-124
Gastrointestinal stromal tumors of the stomach rarely harbour
KIT exon 9 mutations and are mostly associated with a low or no
malignant potential
H . Löser 1 , S . Huss 1 , W . Jeske 1 , M . Fielenbach 1 , P . Hohenberger 2 , P . Reichardt 3 ,
H .-U . Schildhaus 1 , R . Büttner 1 , E . Wardelmann 1
1 University of Cologne, Institute of Pathology, Köln, 2 University of Heidelberg,
Department of Surgery, Mannheim, 3 Helios Klinikum, Hematology/
Oncology, Bad Saarow
Aims. Gastrointestinal stromal tumors (GISTs) are the most common
mesenchymal tumors in the gastrointestinal (GI) tract. Up to 90% of
them carry an activating mutation in the KIT or the PDGFRA (platelet-derived
growth factor alpha) gene both encoding type III receptor
tyrosine kinases. In both genes, hot spot regions have been identified,
i.e. exons 9, 11, 13, and 17 in KIT and exons 12, 14 and 18 in PDGFRA.
The distribution among these different exons is not balanced. More than
60% of cases carry KIT exon 11 mutations followed by 10 to 15% of tumors
carrying either a KIT exon 9 or a PDGFRA exon 18 mutation. All other
locations are very rare (less than 2% for each exon). The different mutational
subtypes in KIT and PDGFRA are found in variable frequences in
different parts of the GI tract. In detail, KIT exon 9 mutations are nearly
always found in the small bowel and rectum and but only rarely in gastral
GISTs. In contrast, PDGFRA mutations are nearly always restricted
to gastric GISTs. We were interested to know how often stomach tumors
carry KIT exon 9 mutations and whether there is an association with an
aggressive behavior as demonstrated for GISTs in a non-gastric location.
Methods. We evaluated more than 2000 cases in our GIST and Sarcoma
Registry Cologne/Bonn (GSRCB) for gastric GISTs with KIT exon 9
mutations. Sequences were analysed by direct Sanger Sequencing. We
evaluated pathomorphological and clinical data and compared them to
GISTs in other primary locations.
Results. We could identify 19 gastric cases carrying a KIT exon 9 mutation.
The average tumor diameter was 4.1 cm. According to the AFIP
classification (Miettinen 2006), 15 tumors belonged to the groups of no or
low aggressive behavior. Three GISTs were classified as high risk lesions
with a mitotic count of 13, 25 and 132/50 HPFs, resp. one other belonged to
the intermediate risk group. 18 tumors carried the classical 6 base pairs
insertion in KIT exon 9 (p.A502_Y503dup). One low-risk tumor showed
a novel 12 bp deletion in KIT exon 9 (p.K484_G487del) which has not
been described before.
Conclusions. KIT exon 9 mutations (typically a 6 bp insertion; p.A502_
Y503dup) occur preferentially in a non-gastric location of GISTs. In these,
the mutational subtype frequently implicates an aggressive behavior.
In contrast, gastric tumors with exon 9 mutation often are associated
with a low or no malignant potential. Conclusively, in the vast majority
of these lesions there is no implication for an adjuvant treatment with
imatinib.
DO-125
Functional phosphoproteomics for therapy response prediction
in malignant thymomas and thymic carcinomas
S . Küffer1 , A .-L . Bohlender1 , C . Sauer1 , D . Belharazem1 , A . Marx1 , P . Ströbel1 1University Medical Centre Mannheim of the University of Heidelberg/Institute
of Pathology, Mannheim
Aims. Thymomas (TH) and thymic carcinomas (TC) are rare mediastinal
tumor with a high tendency for local therapy failures. Relapsed
tumors require first or second line adjuvant treatments, which are not
well established. Our group has recently reported clinical response to
the multikinase inhibitor sunitinib in a small series of patients with metastatic
TC. In an attempt to better understand the underlying molecular
conditions and to eventually predict sunitinib response, we investigated
TH and TC by different phosphoproteomic approaches.
46 | Der Pathologe · Supplement 1 · 2012
Methods. Functional kinomics were carried out by spiking sunitinib into
a tumor lysate from one patient with clinical response to sunitinib and
from one patient with a resistant tumor and subsequent measurement
of 144 receptor tyrosine kinase (RTK) substrates. Snap-frozen tumour
tissues of 63 TH and TC samples were analyzed using Phospho-Protein-
Arrays to detect activation of RTKs and MAPKs. Subsequently, primary
cells from 10 tumor samples with known RTK/MAPK activation status
were tested with sunitinib, an Akt inhibitor and a JNK inhibitor.
Results. Comparing the clinical responder and the non-responder,
44/144 peptide substrates were found a) significantly inhibited by sunitinib
and b) significantly different between the two samples. Pathway analysis
revealed a prominent role of the EGFR, and to some extent, VEGFR
signalling pathways, with involvement of PI3K and ras/raf as downstream
targets. Analysis of a large number of TH and TC revealed activation
of the EGFR alone or in combination with other RTKs in 40/63 cases
(63%). Analysis of MAPK revealed a dichotomic pattern with actvation
of the PI3K/AKT pathway in 46% and activation of JNK kinases in 54%
of cases. Preliminary data with ex vivo cell cultures from TH and TC
treated with AKT and JNK inhibitors suggested better responses to AKT
inhibitors in the “AKT group” and vice versa.
Conclusions. Our results suggest that the EGFR – the single most frequently
activated RTK in TH and TC – as well as its downstream effectors
PI3K/AKT and the ERK pathway may be a prominent sunitinib
target in these tumors. Our findings are surprising, since small clinical
trials using targeted EGFR inhibition (e.g. through gefitinib) were disappointing.
Given the possible involvement of the VEGFR, inhibition of
multiple kinases may be a preferable therapeutic approach. Our results
also indicate that inhibition of specific pathways (such as the AKT) in
highly selected patients may further improve therapeutic response rates.
Workshop Informatik – Strukturierte Befunde
DO-001b
Structured reports in pathology – current status and activities
T . Schrader1 , F . Oemig2 , J . Thümmler 3 , U . Altmann4 , G . Haroske5 1University of Applied Sciences Brandenburg, FB Informatics & Media,
Brandenburg, 2Agfa Healthcare, Standards and Interoperability, 3Vivantes GmbH, Berlin, Ressort IT/TK, 4Justus-Liebig-Universität Gießen, Institut für
Medizinische Informatik, 5Krankenhaus Dresden-Friedrichstadt, Institut für
Pathologie
Aims. The application of structured reports (SR) is a pestering request of
clinicians, tumor centers, tumor registers and pathologists. In various
countries (especially France and Spain) SR’s were developed under the
auspices of IHE (Integrating the Healthcare Enterprises) which influences
the current discussion of standards development. In Germany new
efforts were done to promote the adoption of SR in Pathology and to govern
the National and International activities.
Methods. The current situation in application and development of SR’s
were analyzed. Together with the Federal Society of German Pathologist
and with experts from the German Society of Tumor Centers HL7
Germany has identified information blocks of a SR which are then restructured
into new templates. They are then compared with current IHE
Anatomic Pathology Structured Report (APSR).
Results. HL7 Germany coordinates together with the German Society of
Tumor Centers a comprehensive balloting process in order to establish
Pathology reports. As result of this balloting, different templates of Pathology
reports will be approved and could be implemented by vendors
of Pathology Laboratory Information Systems.
Conclusions. A German implementation guide for CDA-based pathology
reports based on APSR is in development including a German description
on how to use diagnostic terms and classifications, esp. ICD-10 and
TNM.