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A.V. Rüsseler,
B. Brors,
T. Fischer,
J.T. Hartmann,
W. Hartmann,
P. Hohenberger,
P. Lichter,
A. Marx,
G. Mechtersheimer,
R. Penzel,
M. Renner, H.-U. Schildhaus,
P. Schirmacher,
E. Sievers,
P. Ströbel,
E. Wardelmann,
E. Ziesché,
R. Büttner
[show abstract]
[hide abstract]
ABSTRACT: Zur präzisen Diagnostik von Sarkomen und Behandlung in spezialisierten Zentren hat sich mit Förderung durch die Deutsche Krebshilfe
(DKH) der Sarkomforschungsverbund KoSar (Kompetenznetz Sarkome) gebildet. Dieser hat sowohl ein Sarkomgewebearchiv als auch
ein Referenzzentrum gegründet, welches mittlerweile etwa 1000 präzise diagnostizierte Sarkome verschiedener Entitäten enthält.
Mithilfe dieser Proben konnten u.a. signifikante Genexpressionsprofile für synoviale Sarkome, Leiomyosarkome, myxoide Liposarkome
und ein kleines Expressionsprofil für Myxofibrosarkome definiert sowie eine neue Klassifikation der Angiosarkome ableitet
werden. Parallel wurden aktivierte Signaltransduktionswege und molekulare Targets für selektive Therapien in Sarkomzelllinien
und Xenograft-Transplantations-Modellen identifiziert. Hierauf basierend konnten erste klinische Studien mithilfe der Deutschen
Interdisziplinären Sarkom-Studiengruppe (GISG) initiiert werden.
To establish precise diagnostic algorithms and standardised treatment of sarcomas in specialized centers, the interdisciplinary
research group KoSar (sarcoma competence network) has been funded by German Cancer Aid. A sarcoma tissue repository and a
diagnostic reference center have been set up, presently containing about 1000 accurately diagnosed sarcomas of different entities.
Significant gene expression profiles for synovial sarcomas, leiomyosarcomas, myxoid liposarcomas and a small profile for myxofibrosarcomas
as well as a new classification of angiosarcomas were defined. We systematically searched for activated signal transduction
pathways in sarcoma cell lines and xenograft transplant models and candidate targets for molecular therapies were identified.
Based on these results first clinical studies have been initiated by the German Interdisciplinary Sarcoma Study Group (GISG).
StichwörterKoSar-Sarkom-Molekulare Diagnostik-Genexpression-Deutsche Interdisziplinäre Sarkom-Studiengruppe
KeywordsResearch-Sarcoma-Molecular diagnostics-Gene expression-Drug evaluation, preclinical
Der Pathologe 05/2012; 31:211-214. · 0.67 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Aufgrund einer großen multizentrischen Phase-III-Studie (ToGA) wurde Trastuzumab für das metastasierte Adenokarzinom des Magens
und des ösophagogastralen Übergangs in der Kombinationstherapie von der EMEA zugelassen. Voraussetzung ist der Nachweis einer
Her2-Überexpression definiert durch IHC2+ und ein positives FISH-Ergebnis (Ratio ≥2,0) oder durch IHC3+. Die immunhistochemische
Bestimmung (IHC) des Her2-Status unterscheidet sich in zentralen Punkten vom Mammakarzinom: 1.IHC2+/3+ werden auch bei inkompletter
Membranfärbung diagnostiziert, vorausgesetzt diese ist bereits bei Lupenvergrößerung (3+) oder bei mittlerer Vergrößerung
(10:1, 20:1, 2+) zweifelsfrei nachweisbar. 2.Nur bei Resektaten ist zusätzlich darauf zu achten, dass mindestens 10% der
Tumorzellen eine Membranfärbung der entsprechenden Intensität aufweisen. Die Auswertung der Her2-in-situ-Hybridisierung (ISH)
ist an die Regeln beim Mammakarzinom angelehnt (Amplifikation ab Ratio ≥2,0). Definiert man IHC 3+ und IHC2+/FISH+-Fälle
als HER2-positiv, so liegt die Positivitätsrate bei etwa 16%, typischerweise in intestinal differenzierten Karzinomabschnitten.
Da das Magenkarzinom im Unterschied zum Mammakarzinom in bis zu einem Drittel ein heterogenes Her2-Verteilungsmuster aufweist,
sind Lichtmikroskopie-basierte ISH-Verfahren insbesondere beim Auffinden amplifizierter Foci tendenziell der FISH-Analyse
überlegen.
Based on data from a large multicenter phase III trial (ToGA study) trastuzumab has very recently been approved by the EMEA
for metastatic gastric cancer and adenocarcinoma of the gastro-esophageal junction. Only patients with tumors which over express
Her2 as defined by IHC2+ and a confirmatory FISH+ result, or IHC 3+, determined by an accurate and validated assay are eligible
for trastuzumab therapy. However, testing of Her2 status by immunohistochemistry (IHC) differs from breast cancer in core
aspects: 1. IHC2+/3+ is scored even though membranous staining is incomplete if membrane staining is clearly detectable even
at low magnification (2.5x/5x, 3+) or medium magnification (10x/20x, 2+). 2. Additionally, membrane staining at the appropriate
intensity found in at least 10% of tumor cells is restricted to resection specimens. Evaluation of Her2 in situ hybridization
(ISH) is similar to breast cancer with ratio values of ≥2.0 indicating Her2 gene amplification. Taking these modifications
into account and defining the HER2 positive subgroup as IHC 3+ and IHC2+/FISH+, approximately 16% of gastric cancers are considered
Her2 positive, affecting mainly tumor regions with intestinal (gland forming) type carcinoma. In contrast to breast cancer,
up to one-third of gastric cancers show a heterogeneous Her2 status both at IHC and ISH levels which favors bright field ISH
over FISH.
SchlüsselwörterHer2-Diagnostik-Immunhistochemie-Fluoreszenz-in-situ-Hybridisierung-Magenkarzinom
KeywordsHER2 testing-Immunohistochemistry-Fluorescence in situ hybridization-Gastric carcinoma
Der Pathologe 05/2012; 31(3):208-217. · 0.67 Impact Factor
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Der Pathologe 05/2012; 32(1):5-7. · 0.67 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Die Nutzung moderner molekularbiologischer Methoden hat in den letzten Jahren in der Sarkomdiagnostik an Bedeutung gewonnen.
Jede der hier beschriebenen analytischen Methoden hat ihre spezifischen Vorteile, aber auch Anforderungen an das Untersuchungsmaterial.
Zytogenetische Screening-Methoden geben Auskunft über das gesamte Genom, Nachteil ist der Bedarf an Frischgewebe. Durch Fluoreszenz-in-situ-Hybridisierung
und Real-time-Polymerase-Ketten-Reaktion können spezifische genetische Ereignisse, wie Translokationen im Ewing-Sarkom, im
Synovialsarkom oder im alveolären Rhabdomyosarkom in frischen und formalinfixierten Geweben detektiert werden, aber auch Genamplifikationen
im hochdifferenzierten und dedifferenzierten Liposarkom oder strahleninduzierten Angiosarkom sowie Deletionen im Rhabdoidtumor
und im hochdifferenzierten spindelzelligen Liposarkom. Molekularbiologische Methoden wie Sanger-Sequenzierung, Pyrosequenzierung
und die hochauflösende Schmelzpunktanalyse können zur Aufdeckung spezifischer molekularer Aberrationen auf Genebene beitragen.
Dieser Artikel gibt eine Übersicht über die wichtigsten molekularbiologischen Methoden, die zurzeit in der Sarkomdiagnostik
genutzt werden, ihre Bedeutung für die Differenzialdiagnose dieser Tumoren und zeigt Anwendungsbeispiele auf.
The use of modern molecular techniques has gained importance in the diagnosis of sarcomas in recent years. Each of the analytical
methods discussed here has its unique advantages and specific requirements. Cytogenetic screening methods which provide genome-wide
information depend on the availability of fresh tissue. With the aid of fluorescence in situ hybridization and RT-polymerase
chain reaction, specific events such as translocations in Ewing sarcoma, synovial sarcoma or alveolar rhabdomyosarcoma, as
well as gene amplifications in well-differentiated and dedifferentiated liposarcoma or radiation-induced angiosarcoma and
deletions in rhabdoid tumors or well-differentiated spindle cell liposarcoma can be detected in fresh and formalin fixed tissues.
Molecular methods including Sanger sequencing, pyrosequencing and high resolution melting provide information about specific
molecular aberrations on gene level. Here we review the most important molecular techniques currently used in sarcoma diagnosis,
describe their relevance for differential diagnosis and point out specific examples.
SchlüsselwörterSarkome–Translokation–Fluoreszenz-in-situ-Hybridisierung–Real-time-Polymerase-Ketten-Reaktion–Amplifikation
KeywordsSarcoma–Translocation–Fluorescence in situ hydridization–Real-time polymerase chain reaction–Amplification
Der Pathologe 04/2012; 32(1):24-31. · 0.67 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Gastrointestinale Stromatumoren (GIST) sind die häufigsten mesenchymalen Tumoren des Verdauungstrakts. Etwa zwei Drittel der
Tumoren entstehen im Magen, knapp ein Drittel im Dünndarm und die übrigen im Rektum oder sehr selten im Ösophagus. GIST nehmen
ihren Ausgang von der glattmuskulären Wandung des tubulären Gastrointestinaltrakts und wachsen zumeist in Richtung Serosa
vor, deutlich seltener hingegen in Richtung Mukosa. Im letzteren Fall kann es zu einer Ulzeration kommen, die zu einer gastrointestinalen
Blutung als Leitsymptom führen kann. Häufiger sind GIST des Magens aber symptomfrei und daher bei Erstdiagnose schon groß.
Durch das häufig nach außen gerichtete Wachstum sind gastrale GIST endoskopisch zumeist nicht sichtbar und nur endosonographisch
darstellbar. Auch die bioptische Diagnosesicherung ist hierdurch erschwert bis unmöglich. GIST des Magens unterscheiden sich
von Tumoren anderer Primärlokalisation im Hinblick auf ihre Morphologie, ihre Molekularpathologie und ihre Prognose. Die vorliegende
Übersicht gibt einen Überblick über diese Besonderheiten auch im Hinblick auf mögliche therapeutische Konsequenzen.
Gastrointestinal stromal tumors (GIST) are the most frequent mesenchymal tumors of the gastrointestinal tract. Two thirds
of them are located in the stomach, another 30% occur in the small bowel, while the remaining tumors occur in the rectum or
more rarely in the oesophagus. GIST most commonly grow from the smooth muscular layer towards the serosal surface whereas
development towards to the mucosal layer is less frequent. In the latter case ulceration may occur, leading to gastrointestinal
bleeding as the main symptom. However, the majority of GIST of the stomach are asymptomatic, resulting in large tumors on
initial diagnosis. Most gastric GIST are not visible on endoscopy but may be diagnosed by endosonography. Due to their location
in the outer layers of the tubular gastrointestinal tract biopsy is often hindered of even impossible. GIST of the stomach
differ from tumors in other locations with regard to their morphology, molecular pathology and prognosis. This present article
provides an overview of these differences also with regard to possible therapeutic consequences.
SchlüsselwörterGastrointestinale Stromatumoren (GIST)-
KIT-Mutation-
PDGFRα-Mutation-Magen-Imatinib
KeywordsGastrointestinal stromal tumors (GIST)-
KIT mutation-
PDGFRα mutation-Stomach-Imatinib
Der Pathologe 04/2012; 31(3):195-198. · 0.67 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: HintergrundInflammatorische fibroide Polypen (IFP) sind Proliferationen CD34-positiver Spindelzellen vor einem inflammatorischen Hintergrund
in der Submukosa und Mukosa des Gastrointestinaltrakts. IFP kommen vor allem im Magen, aber auch im Dünndarm, Kolon und Ösophagus
vor. Ätiologie und Pathogenese sind bislang unklar.
Material und Methoden29 IFP aus Magen, Dünn- und Dickdarm wurden immunhistochemisch und molekularpathologisch untersucht. Für die Exons 10, 12,
14 und 18 von PDGFRA wurden Mutationsanalysen durchgeführt.
ErgebnisseIn 20Fällen (69%) wurden aktivierende Mutationen in den Exons 12 und 18 gefunden. Die Mutationstypen entsprachen dabei sämtlich
bereits von gastrointestinalen Stromatumoren (GIST) bekannten aktivierenden Mutationen. D842V war der häufigste Mutationstyp.
In den Exons 10 und 14 wurden keine aktivierenden Mutationen nachgewiesen.
SchlussfolgerungenDie Mehrzahl der IFP weist aktivierende Mutationen in PDGFRA auf. Dieser Befund spricht dafür, dass es sich um echte Neoplasien (echte benigne Tumoren) und nicht um reaktive Läsionen
handelt. Die Beziehungen zwischen PDGFRA-mutierten GISTs und IFP im Hinblick auf die Pathogenese sind noch unklar.
AimsInflammatory fibroid polyps (IFP) are proliferations of CD34-positive spindle cells in the submucosa and mucosa of the gastrointestinal
tract with an inflammatory infiltrate. IFP occur in the stomach, small bowel, colon and esophagus. To date, etiology and pathogenesis
are unclear.
MethodsA total of 29 IFP originating in the stomach, small bowel and colon were examined immunohistochemically, and mutational analyses
of PDGFRA exons 10, 12, 14 and 18 were conducted.
ResultsActivating mutations in PDGFRA exons 12 and 18 were found in 20 cases (69%). The mutational types are related to mutations known from gastrointestinal stromal
tumors (GIST). D842V was the most frequent mutation. No activating mutations were found in exons 10 and 14.
ConclusionsThe majority of IFP reveal activating PDGFRA mutations. Our data indicate that IFP are true neoplasms (true benign tumors) and not reactive lesions. In terms of pathogenesis,
the relationship between PDGFRA-mutant GISTs and IFP remains to be determined.
Der Pathologe 04/2012; 30:117-120. · 0.67 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Gastrointestinale Stromatumoren (GIST) zeigen in etwa 50% der Fälle einen aggressiven Phänotyp mit Rezidiven und Metastasen.
Sie können immunhistochemisch sicher von anderen mesenchymalen Tumorentitäten unterschieden werden und tragen in bis zu 85%
der Fälle aktivierende Mutationen in den Rezeptortyrosinkinasen KIT oder PDGFRA. Die Aufklärung ihrer molekularen Pathogenese
hatte einen therapeutischen Paradigmenwechsel zur Folge. Bei inoperablen oder metastasierten GIST stellt die Behandlung mit
Tyrosinkinaseinhibitoren heute den Goldstandard dar mit einer Ansprechrate von bis zu 80% bei vergleichsweise geringen Nebenwirkungen.
Die Kenntnis der KIT- bzw. PDGFRA-Mutation ist dabei sowohl prognostisch als auch therapeutisch von zentraler Bedeutung.
Gastrointestinal stromal tumors (GIST) show an aggressive behavior with metastases and recurrences in up to 50% of cases.
They can be clearly distinguished from other mesenchymal tumors by immunohistochemistry in the vast majority of cases. Of
the tumors 85% carry somatic activating mutations in the receptor tyrosine kinases KIT or PDGFRA. The detection of these molecular
events has changed the treatment of inoperable and metastatic GISTs dramatically as up to 80% of tumors respond well to tyrosine
kinase inhibitors. This treatment has become the gold standard in the last few years with only few side effects. Knowledge
of the underlying KIT or PDGFRA mutation is both relevant for the prognosis and treatment response.
Der Radiologe 04/2012; 49(12):1104-1108. · 0.61 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Inflammatorische fibroide Polypen (IFP) wurden vor 60Jahren von Vaněk erstmals als „submuköses Granulom mit eosinophiler
Infiltration“ beschrieben. IFP stellen polypöse Spindelzellproliferate in der Submukosa und Mukosa von Magen, Dünndarm und
Kolon mit entzündlicher Infiltration dar. Die Läsion ist bislang als entzündlich-reaktiv angesehen worden. Neuere Daten zeigen,
dass die läsionalen Spindelzellen den PDGFRA exprimieren, in der Mehrzahl der Fälle sind aktivierende PDGFRA-Mutationen nachweisbar. IFP sind also echte benigne mesenchymale Tumoren des Gastrointestinaltrakts.
Inflammatory fibroid polyps (IFP) were described by Vaněk 60years ago as “submucosal granuloma with eosinophilic infiltration”.
IFP represent polypous proliferations of spindle cells in the submucosa and mucosa of the stomach, small bowel and colon with
inflammatory infiltration. The lesions have been regarded as inflammatory and reactive. Recent data show that the spindle
cells express PDGFRA, and the majority of IFP harbour activating PDGFRA mutations. Therefore, IFP represent true benign mesenchymal tumors of the gastrointestinal tract.
SchlüsselwörterInflammatorischer fibroider Polyp-Gastrointestinaltrakt-
PDGFRA-Mutation-Gastrointestinale Stromatumoren
KeywordsInflammatory fibroid polyp-Gastrointestinal tract-
PDGFRA mutation-GIST
Der Pathologe 04/2012; 31(2):109-114. · 0.67 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Postradiation cutaneous vascular lesions after treatment of breast carcinoma comprise a heterogeneous group of benign, atypical, and malignant lesions and are best regarded as points along a morphological spectrum. We analyzed a series of cutaneous angiosarcomas after treatment of breast cancer in comparison with control cases and cases of atypical vascular lesions with special emphasis on the expression and amplification of MYC. The 66 cases were divided into control cases (5), cases in which a slight vascular proliferation was seen after radiotherapy of breast cancer (12), cases of atypical vascular lesions after radiotherapy (16), cases of postradiation cutaneous angiosarcomas (25), and cases of angiosarcomas of skin and soft tissues unrelated to radiotherapy (8). None of the control cases (2 M, 3 F, 20-76 years), of cases showing slight vascular proliferation, dermal fibrosis and inflammation after radiotherapy of breast cancer (12 F, 48-79 years), of cases of atypical vascular lesions after radiotherapy (16 F, 29-81 years), and of cases of angiosarcomas of skin and soft tissues unrelated to radiotherapy (3 M, 5 F, 25-92 years) showed an amplification of MYC by FISH analysis. In striking contrast, in all cases of postradiation cutaneous angiosarcomas (25 F, 46-95 years), MYC amplification was found by FISH analysis in a variable number of counted nuclei. Immunohistochemically, strong positive nuclear staining for MYC and prox-1 was seen in cases of postradiation cutaneous angiosarcoma, whereas control cases and cases of atypical vascular proliferation after radiotherapy were negative for MYC, and stained only focally positive for prox-1 in a number of cases. In conclusion, the presence of MYC amplification represents an important additional diagnostic tool in the distinction of postradiation cutaneous angiosarcomas from atypical vascular lesions after radiotherapy. Immunohistochemical stainings for MYC are useful for mapping of these lesions and for careful tumor margin control.
Modern Pathology 09/2011; 25(1):75-85. · 4.79 Impact Factor
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Der Pathologe 02/2011; 32(1):5-7. · 0.67 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Due to their rarity and multiple subtypes, there is scant experience with sarcomas. Any effective targeted therapy depends on precise diagnosis of the tumor group using molecular markers and, increasingly, mutation testing. The necessary histopathological expertise and molecular diagnostic tools are usually only found at specialized centers. Using the Bonner GIST register as an example, the advantages of this kind of register from a diagnostic and therapeutic perspective will be discussed. Material submitted for gastrointestinal stromal tumors and other mesenchymal tumors, as well as the supervision of pathological referencing for national and international studies have made accurate diagnosis and appropriate therapy strategies ever more possible. The introduction of epidemiological as well as interdisciplinary sarcoma registers is a prerequisite for the improvement of sarcoma diagnostics and therapy.
Der Pathologe 11/2010; 32(1):72-5. · 0.67 Impact Factor
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A V Rüsseler,
B Brors,
T Fischer,
J T Hartmann,
W Hartmann,
P Hohenberger,
P Lichter,
A Marx,
G Mechtersheimer,
R Penzel,
M Renner, H-U Schildhaus,
P Schirmacher,
E Sievers,
P Ströbel,
E Wardelmann,
E Ziesché,
R Büttner
[show abstract]
[hide abstract]
ABSTRACT: To establish precise diagnostic algorithms and standardised treatment of sarcomas in specialized centers, the interdisciplinary research group KoSar (sarcoma competence network) has been funded by German Cancer Aid. A sarcoma tissue repository and a diagnostic reference center have been set up, presently containing about 1000 accurately diagnosed sarcomas of different entities. Significant gene expression profiles for synovial sarcomas, leiomyosarcomas, myxoid liposarcomas and a small profile for myxofibrosarcomas as well as a new classification of angiosarcomas were defined. We systematically searched for activated signal transduction pathways in sarcoma cell lines and xenograft transplant models and candidate targets for molecular therapies were identified. Based on these results first clinical studies have been initiated by the German Interdisciplinary Sarcoma Study Group (GISG).
Der Pathologe 10/2010; 31 Suppl 2:211-4. · 0.67 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: During the past few years, differential diagnosis of soft tissue tumours has improved due to novel molecular diagnostic tools. Besides a better differentiation between different tumour entities the recognition of specific molecular aberrations may also help to identify novel therapeutic targets. One of the most promising examples of effective molecularly driven treatment is the gastrointestinal stromal tumour. Shortly after the detection of gain-of-function mutations in the type III receptor tyrosine kinases KIT and PDGFRα a targeted treatment with the tyrosine kinase inhibitor imatinib was introduced and became the gold standard in advanced GIST disease. The success of this therapy with response rates of >80% stable disease and partial remission is still unmatched. Since then, many groups aim to identify other potential molecular targets. Genomic and proteomic signatures may pinpoint potential areas of interest for diagnostic tools, prediction of clinical outcome and potential response to therapeutic targets. This article gives an overview of the most important genomic aberrations in sarcomas, their differential diagnosis and the relevance of molecular biology for treatment strategies.
Annals of Oncology 10/2010; 21 Suppl 7:vii265-9. · 6.43 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The use of modern molecular techniques has gained importance in the diagnosis of sarcomas in recent years. Each of the analytical methods discussed here has its unique advantages and specific requirements. Cytogenetic screening methods which provide genome-wide information depend on the availability of fresh tissue. With the aid of fluorescence in situ hybridization and RT-polymerase chain reaction, specific events such as translocations in Ewing sarcoma, synovial sarcoma or alveolar rhabdomyosarcoma, as well as gene amplifications in well-differentiated and dedifferentiated liposarcoma or radiation-induced angiosarcoma and deletions in rhabdoid tumors or well-differentiated spindle cell liposarcoma can be detected in fresh and formalin fixed tissues. Molecular methods including Sanger sequencing, pyrosequencing and high resolution melting provide information about specific molecular aberrations on gene level. Here we review the most important molecular techniques currently used in sarcoma diagnosis, describe their relevance for differential diagnosis and point out specific examples.
Der Pathologe 10/2010; 32(1):24-31. · 0.67 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Based on data from a large multicenter phase III trial (ToGA study) trastuzumab has very recently been approved by the EMEA for metastatic gastric cancer and adenocarcinoma of the gastro-esophageal junction. Only patients with tumors which over express Her2 as defined by IHC2+ and a confirmatory FISH+ result, or IHC 3+, determined by an accurate and validated assay are eligible for trastuzumab therapy. However, testing of Her2 status by immunohistochemistry (IHC) differs from breast cancer in core aspects: 1. IHC2+/3+ is scored even though membranous staining is incomplete if membrane staining is clearly detectable even at low magnification (2.5x/5x, 3+) or medium magnification (10x/20x, 2+). 2. Additionally, membrane staining at the appropriate intensity found in at least 10% of tumor cells is restricted to resection specimens. Evaluation of Her2 in situ hybridization (ISH) is similar to breast cancer with ratio values of > or =2.0 indicating Her2 gene amplification. Taking these modifications into account and defining the HER2 positive subgroup as IHC 3+ and IHC2+/FISH+, approximately 16% of gastric cancers are considered Her2 positive, affecting mainly tumor regions with intestinal (gland forming) type carcinoma. In contrast to breast cancer, up to one-third of gastric cancers show a heterogeneous Her2 status both at IHC and ISH levels which favors bright field ISH over FISH.
Der Pathologe 05/2010; 31(3):208-17. · 0.67 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Inflammatory fibroid polyps (IFP) were described by Vanek 60 years ago as "submucosal granuloma with eosinophilic infiltration". IFP represent polypous proliferations of spindle cells in the submucosa and mucosa of the stomach, small bowel and colon with inflammatory infiltration. The lesions have been regarded as inflammatory and reactive. Recent data show that the spindle cells express PDGFRA, and the majority of IFP harbour activating PDGFRA mutations. Therefore, IFP represent true benign mesenchymal tumors of the gastrointestinal tract.
Der Pathologe 03/2010; 31(2):109-14. · 0.67 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Gastrointestinal stromal tumors (GIST) are the most frequent mesenchymal tumors of the gastrointestinal tract. Two thirds of them are located in the stomach, another 30% occur in the small bowel, while the remaining tumors occur in the rectum or more rarely in the oesophagus. GIST most commonly grow from the smooth muscular layer towards the serosal surface whereas development towards to the mucosal layer is less frequent. In the latter case ulceration may occur, leading to gastrointestinal bleeding as the main symptom. However, the majority of GIST of the stomach are asymptomatic, resulting in large tumors on initial diagnosis. Most gastric GIST are not visible on endoscopy but may be diagnosed by endosonography. Due to their location in the outer layers of the tubular gastrointestinal tract biopsy is often hindered of even impossible. GIST of the stomach differ from tumors in other locations with regard to their morphology, molecular pathology and prognosis. This present article provides an overview of these differences also with regard to possible therapeutic consequences.
Der Pathologe 02/2010; 31(3):195-8. · 0.67 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Inflammatory fibroid polyps (IFP) are proliferations of CD34-positive spindle cells in the submucosa and mucosa of the gastrointestinal tract with an inflammatory infiltrate. IFP occur in the stomach, small bowel, colon and esophagus. To date, etiology and pathogenesis are unclear.
A total of 29 IFP originating in the stomach, small bowel and colon were examined immunohistochemically, and mutational analyses of PDGFRA exons 10, 12, 14 and 18 were conducted.
Activating mutations in PDGFRA exons 12 and 18 were found in 20 cases (69%). The mutational types are related to mutations known from gastrointestinal stromal tumors (GIST). D842V was the most frequent mutation. No activating mutations were found in exons 10 and 14.
The majority of IFP reveal activating PDGFRA mutations. Our data indicate that IFP are true neoplasms (true benign tumors) and not reactive lesions. In terms of pathogenesis, the relationship between PDGFRA-mutant GISTs and IFP remains to be determined.
Der Pathologe 09/2009; 30 Suppl 2:117-20. · 0.67 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Gastrointestinal stromal tumors (GIST) show an aggressive behavior with metastases and recurrences in up to 50% of cases. They can be clearly distinguished from other mesenchymal tumors by immunohistochemistry in the vast majority of cases. Of the tumors 85% carry somatic activating mutations in the receptor tyrosine kinases KIT or PDGFRA. The detection of these molecular events has changed the treatment of inoperable and metastatic GISTs dramatically as up to 80% of tumors respond well to tyrosine kinase inhibitors. This treatment has become the gold standard in the last few years with only few side effects. Knowledge of the underlying KIT or PDGFRA mutation is both relevant for the prognosis and treatment response.
Der Radiologe 09/2009; 49(12):1104-8. · 0.61 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Inflammatory fibroid polyps (IFPs) are mesenchymal tumours which arise in the submucosa and mucosa of the gastrointestinal tract. To date, the pathogenesis is unknown and IFPs are considered reactive and non-neoplastic lesions. Investigating a series of 23 IFPs, we made the observation that the tumours consistently express PDGFRA. To further elucidate the pathogenetic role of PDGFRA, we performed mutational analyses of exons 10, 12, 14, and 18. As IFPs are characterized by an inflammatory infiltrate rich in eosinophils, we used fluorescence in situ hybridization in a subset of tumours to investigate a possible FIP1L1-PDGFRA translocation which is known as the cause of hypereosinophilic syndrome (HES). Sixteen IFPs (70%) harboured activating mutations in exons 12 and 18, respectively: V561D (n = 1), R560SDelta561-567 (n = 1), Delta559-561D591H (n = 1), S566RDelta567-571 (n = 3), D842V (n = 7), D842I (n = 1), Delta842-845 (n = 1), and Delta845-848 (n = 1). These mutations equal pathogenic mutations detected in gastrointestinal stromal tumours previously. Activating mutations in exons 10 and 14 were not noted. None of the cases revealed the FIP1L1-PDGFRA translocation. Considering the remarkable number of activating mutations detected in our series, we conclude that the vast majority of IFPs harbour gain-of-function mutations in the PDGFRA gene. The presence of PDGFRA mutations questions the reactive nature of IFPs and raises the possibility of a neoplastic process.
The Journal of Pathology 10/2008; 216(2):176-82. · 6.32 Impact Factor
