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Die Abgrenzung reaktiver Mesothellasionen gegenuber neoplastischen Prozessen des Mesothels innerhalb einer Hydrocele testis kann diagnostische Schwierigkeiten bereiten. Die immunhistochemische Analyse allein ist hier haufig nicht richtungsweisend, jedoch ist fur die Kombination der immunhistochemischen Bestimmung von BAP1 und der FISH-Analyse von CDKN2A> eine hohe Spezifitat und Sensitivitat bezuglich dieser Differenzialdiagnose dokumentiert. Eine weitere wichtige Hilfestellung ist die Anamnese von Risikofaktoren wie Asbestbelastung und zuruckliegende Traumata. Entscheidend fur die korrekte Diagnosestellung einer reaktiven Mesothellasion ist der Ausschluss von Invasivitat anhand ausgedehnter Gewebeaufarbeitung.

More than 20% of soft-tissue tumors belong to the group of adipocytic neoplasms. Difficulties may occur in the differential diagnosis of lipomas versus atypical lipomatous tumors/well-differentiated liposarcomas, in the distinction of dedifferentiated liposarcomas from other soft-tissue sarcoma entities and in the detailed subtyping of liposarcomas. Especially in biopsies, the correct diagnosis and grading may be hampered due to limited tissue. Because of the ever-increasing molecular-pathological knowledge of soft-tissue tumors and the rising distribution of molecular diagnostic assays in institutes of pathology, differential diagnosis has been facilitated, as more than 90% of adipocytic tumors carry more or less specific genomic alterations. In the following, the most important subtypes of adipocytic tumors are described morphologically and genomically.

Background In 2004, we started an intergroup randomized trial of adjuvant imatinib versus no further therapy after R0-R1 surgery in localized, high/intermediate-risk gastrointestinal stromal tumors (GIST) patients. Interim analysis results were published in 2015 upon recommendation from an independent data review committee. We report the final outcome of the study. Patients and methods This was a randomized, open-label, multicenter phase III trial carried out at 112 hospitals in 12 countries. Patients were randomized to 2 years of imatinib, 400 mg daily, or no further therapy after surgery. The primary endpoint was imatinib failure-free survival (IFFS), while relapse-free survival (RFS), relapse-free interval (RFI), overall survival (OS) and toxicity were secondary endpoints. Adjusting for the interim analyses, results on IFFS were assessed on a 4.3% significance level; for the other endpoints, 5% was used. Results Nine hundred and eight patients were randomized between January 2005 and October 2008: 454 to imatinib and 454 to observation; 835 patients were eligible. With a median follow-up of 9.1 years, 5 (10)-year IFFS was 87% (75%) in the imatinib arm versus 83% (74%) in the control arm [hazard ratio (HR) = 0.87, 95.7% confidence interval (CI) (0.65; 1.15), P = 0.31]; RFS was 70% versus 63% at 5 years and 63% versus 61% at 10 years, [HR = 0.71, 95% CI (0.57; 0.89), P = 0.002]; OS was 93% versus 92% at 5 years and 80% versus 78% at 10 years [HR = 0.88, 95% CI (0.65; 1.21), P = 0.43]. Among 526 patients with high-risk GIST by local pathology, 10-year IFFS and RFS were 69% versus 61%, and 48% versus 43%, respectively. Conclusions With 9.1 years of follow-up, a trend toward better long-term IFFS in imatinib-treated patients was observed in the high-risk subgroup. Although the difference was not statistically significant and the surrogacy value of such an endpoint is not validated, this may be seen as supporting the results reported by the Scandinavian/German trial, showing a sustained small but significant long-term OS benefit in high-risk GIST patients treated with 3 years of adjuvant imatinib.

Proliferative changes seen in reactive mesothelial hyperplasia of a hydrocele sac may mimic malignant mesothelioma. There is no immunohistochemical staining that reliably separates benign from malignant mesothelial proliferations. However, the combined analysis of BAP1 by immunohistochemistry and CDKN2A by FISH has been reported to yield both a high specificity and sensitivity in this differential diagnosis. In addition, the evaluation of risk factors such as asbestos exposure or prior traumata may be helpful for the correct diagnosis. Exclusion of stromal invasion, which is diagnostic for malign mesothelioma, is of utmost importance. Therefore, extended histological workup is essential.

The concept of arming antibodies with bioactive payloads for a site-specific therapy of cancer has gained considerable interest in recent years. However, a successful antibody-based targeting approach critically relies on the availability of a tumor-associated target that is not only preferentially expressed in the tumor tissue but is also easily accessible for antibody therapeutics coming from the bloodstream. Here, we perfused the vasculature of healthy and acute myeloid leukemia (AML)-bearing rats with a reactive ester derivative of biotin and subsequently quantified the biotinylated proteins to identify AML-associated bone marrow (BM) antigens accessible from the bloodstream. In total, >1400 proteins were identified. Overall, 181 proteins were >100-fold overexpressed in AML as compared with normal BM. Eleven of the most differentially expressed proteins were further validated by immunohistochemistry and confocal microscopic analyses, including novel antigens highly expressed in AML cells (for example, adaptor-related protein complex 3 β2) and in the leukemia-modified extracellular matrix (ECM) (for example, collagen-VI-α-1). The presented atlas of targetable AML-associated BM proteins provides a valuable basis for the development of monoclonal antibodies that could be used as carriers for a site-specific pharmacodelivery of cytotoxic drugs, cytokines or radionuclides to the BM in AML.

More than 20% of soft-tissue tumors belong to the group of adipocytic neoplasms. Difficulties may occur in the differential diagnosis of lipomas versus atypical lipomatous tumors/well-differentiated liposarcomas, in the distinction of dedifferentiated liposarcomas from other soft-tissue sarcoma entities and in the detailed subtyping of liposarcomas. Especially in biopsies, the correct diagnosis and grading may be hampered due to limited tissue. Because of the ever-increasing molecular-pathological knowledge of soft-tissue tumors and the rising distribution of molecular diagnostic assays in institutes of pathology, differential diagnosis has been facilitated, as more than 90% of adipocytic tumors carry more or less specific genomic alterations. In the following, the most important subtypes of adipocytic tumors are described morphologically and genomically.

Das Malignitatsgrading stellt einen wesentlichen Baustein bei der Klassifikation von Sarkomen dar. Es korreliert mit der Prognose der Erkrankung und dem Risiko einer Metastasierung. Der Artikel prasentiert die Gradierungsschemata von Sarkomen der Weichteile, des Knochens und des Kindesalters. Die histomorphologischen Kriterien des FNCLCC-Systems (Federation Nationale des Centres de Lutte Contre le Cancer) und der Pediatric Oncology Group werden ebenso vorgestellt wie das Grading von Knochentumoren nach dem System des College of American Pathologists (CAP). Des Weiteren wird aufgezeigt, inwieweit Genexpressionssignaturen („complexity index in sarcoma“, CINSARC) und einzelne genetische Veranderungen (p53, MDM2, p16, SWI/SNF, EWSR1-Fusionen, PAX3/PAX7-FOXO1-Fusionen) fur die Prognoseeinschatzung von Sarkomen von Bedeutung sein konnen.

Die Obduktion eines Fetus der 23. Schwangerschaftswoche ergab den Befund eines partiellen Perikarddefektes mit einem hernierten Anteil des linken Ventrikels. Mikroskopisch war das Bild bei taillenformigen Einschnurungen des Myokards gepragt durch Zeichen rezidivierend abgelaufener hypoxischer Schadigungen des Myokards mit Nekrosen, scholligen Verkalkungen, Fibrosen und Eisenspeicherungen wie nach abgelaufenen Mikroinfarkten.

Item does not contain fulltext INTRODUCTION: In patients with advanced soft tissue sarcoma (STS) treated with chemotherapy, WHO performance status, histologic subtype and histologic grade are known prognostic factors. Although the difference between the subgroups: locally advanced disease only, metastatic disease only and both local and metastatic disease is easily made, its prognostic relevance is thus far unknown. The aim of this EORTC database study was to study the difference in prognosis between these subgroups in patients receiving first-line chemotherapy for advanced STS. METHODS: A retrospective database analysis was performed on 2473 patients receiving first-line chemotherapy for advanced STS from 12 EORTC sarcoma trials to establish the difference in prognosis for the three subgroups. End-points were overall survival, progression-free survival and overall response rate. Factors studied were age, sex, histologic subtype, histologic grade, WHO performance status, treatment and time since initial diagnosis. RESULTS: Overall survival differed significantly between patients with locally advanced disease only, with metastatic disease only and with both locally advanced and metastatic disease with a median overall survival of 15.4, 12.9 and 10.6 months, respectively. Similar differences were seen for progression-free survival (5.8, 4.3 and 3.2 months, respectively). CONCLUSION: This large retrospective database study shows that patients with advanced STSs treated with first-line chemotherapy with locally advanced disease, metastatic disease and both local and metastatic disease have different outcomes. This should be accounted for in future study design, interpretation and comparison of study results and daily practice.

Invasion and metastatic dissemination of tumor cells defines prognosis not only in patients with epithelial, but also mesenchymal neoplasms. Early and clinically inapparent micrometastases occur in many patients, and the risk for metastasis correlates with the tumor subtype and histologic tumor grade. In recent years and analogous to the situation in epithelial tumors, mechanisms of tumor cell dissemination in soft tissue tumors have been increasingly understood, and it has been shown that reorganization of the actin cytoskeleton plays a key role in these processes. This review summarizes current knowledge on the mechanisms of progression and metastasis of soft tissue tumors and points out possible targets for novel anti-invasive and anti-metastatic therapies.

Auf dem Boden einer Endometriose konnen maligne Tumoren entstehen; dabei fallen etwa 80 % auf Ovarialkarzinome und etwa 20 % auf extragonadale Manifestationen. Diese maligne Transformation kann jedes Gewebe betreffen, in dem auch Endometriose vorkommt. Eine direkte Kanzerisierung benigner Endometriose uber Atypien erscheint moglich. Histologisch handelt es sich bei den endometrioseassoziierten Malignomen uberwiegend um endometrioide oder klarzellige Karzinome, seltener um andere histologische Typen, wie seromuzinose Bordeline-Tumoren, endometriale Stromasarkome, Adenosarkome u. a. Das Risiko einer malignen Transformation von Endometriosegewebe bzw. deren Pravalenz wurde in alteren Arbeiten mit insgesamt 1 % angegeben, bei ovariellen Endometriomen mit 2,5 % bei einer Breite zwischen 2 und 17 %. Molekularbiologisch wurden PTEN- und ARID1a-Mutationen sowie Heterozygotieverlust gefunden. Klinisch wird eine bessere Prognose dieser Tumoren im Vergleich mit high-grade serosen Ovarialkarzinomen diskutiert. Insgesamt liegen in der Literatur nur wenige systematische Studien zu diesen Malignomen vor. Die Stiftung Endometrioseforschung fuhrt gemeinsam mit den Kommissionen Ovar und Uterus der Arbeitsgemeinschaft Gynakologische Onkologie (AGO) aktuell eine retrospektive Studie zur Charakterisierung endometrioseassoziierter Malignome durch (EAM-Studie); ihr Herzstuck ist die histopathologische Zweitbegutachtung in einem Referenzlabor.

Desmoid-type fibromatosis is a rare and locally aggressive monoclonal, fibroblastic proliferation characterized by a variable and often unpredictable clinical course. Currently, there is no established or evidence-based treatment approach available for this disease. Therefore, in 2015 the European Desmoid Working Group published a position paper giving recommendations on the treatment of this intriguing disease. Here, we present an update of this consensus approach based on professionals’ AND patients’ expertise following a round table meeting bringing together sarcoma experts from the European Organization for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group with patients and patient advocates from Sarcoma PAtients EuroNet. In this paper, we focus on new findings regarding the prognostic value of mutational analysis in desmoid-type fibromatosis patients and new systemic treatment options.

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors in the gastrointestinal tract although they are much less frequent than epithelial tumors. In more than 60% of cases they occur in the stomach. Especially small lesions measuring ≤1 cm in diameter, so-called microscopic GIST can occur multifocally, frequently in the proximal stomach wall and sometimes as an incidental finding in a gastrectomy specimen resected for gastric cancer. The multicentricity of GIST alone is not proof of a metastatic behavior or a syndromal or hereditary disease. Multiple sporadic synchronous and metachronous GIST are characterized by different primary mutations mostly in the KIT or PDGFRA genes and are often less aggressive. It is speculative whether a field effect is responsible or whether still unknown GIST-promoting factors may facilitate the development of several independent lesions. If KIT or PDGFRA mutations are lacking, a succinate dehydrogenase (SDH) deficient GIST has to be considered, either hereditary as Carney-Stratakis syndrome or syndromal as part of a Carney triad.

The autopsy of a fetus at 23 weeks gestational age revealed a partial pericardial defect with subsequent herniation of parts of the left ventricle. The myocard was impinged by the fibrous rim of the residual pericardium. Microscopic examination showed signs of recurrent myocardial infarctions with necrosis, calcification, fibrosis and prominent deposition of iron.Partial pericardial defects result from incomplete fusion of the pleuropericardial membrane and may lead to myocardial infarction via compression of the coronary arteries.

Die Inzidenz der Weichteiltumoren des Kopf-Hals-Bereichs ist niedrig: 300/100.000 (benigne) bzw. 3/100.000 Einwohner (maligne). Jedoch bieten besonders Sarkome ein buntes histologisches Bild. Hier wird ein Uberblick uber die an der HNO-Klinik der Autoren behandelten Weichteiltumoren des Kopf-Hals-Bereichs gegeben. Retrospektiv wurden 106 Patienten, die 2002–2010 wegen eines Weichteiltumors behandelt wurden, bezuglich tumor- und patientenspezifischer Daten erfasst (Dignitat, Lokalisation, TNM-, R-Klassifikation, Therapie, Grading). Es wurden 77 benigne Tumoren, 5 Tumoren intermediarer Dignitat und 24 Sarkome mit 7 unterschiedlichen Subtypen identifiziert. Wahrend die benignen und intermediaren Tumoren durch operative Entfernung behandelt wurden, erfolgte in 21 der 24 Sarkome eine multimodale Therapie unter Einschluss von Radio- und/oder Chemotherapie. Wahrend die gutartigen Tumoren mittels Op. sicher zu heilen sind, besteht bei den Sarkomen angesichts der unterschiedlichen histologischen Subtypen keine einheitliche Therapie. Allein die fallbezogene interdisziplinare Zusammenarbeit erlaubt die Aussicht auf eine erfolgreiche Therapie.

Summary Background Inhibitors of the mutated, constitutively activated BRAF protein have shown efficacy in the treatment of metastatic melanoma in clinical trials. Mutation analysis especially of the BRAF, NRAS and KIT genes is essential to identify patients suitable for targeted therapies and has been introduced into routine patient care. Objectives To correlate mutational status with clinical parameters including age, skin type, number of melanocytic naevi, primary tumour location, chronic sun damage and exposure to ultraviolet (UV) irradiation. The overall aim was to define subgroups with an increased or decreased likelihood of gene mutations. Additionally, the impact of activating BRAF mutations on clinical course was investigated. Methods In a single-centre, retrospective approach, mutation analysis was performed on patients with metastatic malignant melanoma. Clinical parameters were correlated with molecular findings. The total sun-burden score was assessed using a validated standardized questionnaire. Results The analysis included 141 patients with metastatic melanoma. Forty-four per cent of patients had activating BRAF mutations and were significantly younger than patients with wild-type BRAF or with NRAS mutations. KIT mutations were detected in only 3% of the patients. BRAF-mutated melanomas developed preferentially in intermittently sun-exposed areas of the body, and patients had significantly more melanocytic naevi. Once patients had progressed into stage IV disease, survival times were identical for those with BRAF-mutated and BRAF wild-type tumours. Conclusions Mutations of the BRAF gene are correlated with younger age, a higher number of melanocytic naevi and a tumour location in intermittently UV-exposed skin. Signs of chronic photodamage are not indicative of mutational status. Patients with metastatic melanoma with BRAF mutations showed a nonsignificant tendency to progress later to stage IV disease, but once metastases were present the prognosis was identical to that with BRAF wild-type tumours.

Malignancy grading is an essential element in the classification of sarcomas. It correlates with the prognosis of the disease and the risk of metastasis. This article presents the grading schemes for soft tissue, bone and pediatric sarcomas. It summarizes the histological criteria of the Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) system and the Pediatric Oncology Group as well as the grading of bone tumors by the College of American Pathologists (CAP). Furthermore, the potential relevance of gene expression signatures, the complexity index in sarcoma (CINSARC) and single genetic alterations (p53, MDM2, p16, SWI/SNF, EWSR1 fusions and PAX3/PAX7-FOXO1 fusions) for the prognosis of sarcomas are discussed.

At present, there is not a commonly used and generally accepted standardized approach for the pathologic evaluation of pretreated soft tissue sarcomas. Also, it is still unclear whether the cut-off for prognostic relevance is similar in the many different histological subtypes of STS. This manuscript, produced by a European Organization for Research and Treatment of Cancer - Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) endorsed task force, aims to propose standardization of the pathological examination process and the reporting of STS resection specimens after neoadjuvant radio- and/or chemotherapy.

Gastrointestinale Stromatumoren (GIST) sind bei Kindern und Jugendlichen sehr selten und unterscheiden sich klinisch und biologisch von GIST des Erwachsenenalters. So konnen die charakteristischen, molekularen Veranderungen [Mutationen in den Rezeptortyrosinkinasegenen KIT und PDGFRA („platelet-derived growth factor receptor alpha“)], die eine zielgerichtete Behandlung dieser chemo- und strahlenresistenten Tumoren mit Rezeptortyrosinkinaseinhibitoren erlauben, bei Kindern und Jugendlichen mit GIST nur sehr selten nachgewiesen werden. Wegen der extremen Seltenheit fehlen standardisierte Richtlinien zum diagnostisch-therapeutischen Vorgehen. Die flachendeckende Registrierung dieser Tumoren im Register fur Weichteilsarkome und seltene Weichteiltumoren (SoTiSaR) ist eine Voraussetzung, um Epidemiologie und Tumorbiologie besser verstehen zu konnen und dient als Grundlage fur die zukunftige Entwicklung von Managementrichtlinien.

To cite this article: Maintz L, Wardelmann E, Walgenbach K, Fimmers R, Bieber T, Raap U, Novak N. Neuropeptide blood levels correlate with mast cell load in patients with mastocytosis. Allergy 2011; 66: 862–869. Abstract Background: Mastocytosis is characterized by abnormal growth and accumulation of mast cells (MCs) in different organs. MCs have been shown to express receptors for neuropeptides. Furthermore, neuropeptides can activate MCs inducing cytokine production and MC mediator release, which further contribute to MC chemotaxis and stimulate the release of vasoactive peptides from sensory nerves. Thus, a contribution of neuropeptides to mastocytosis seems highly conceivable, but has not been investigated sufficiently yet. This study aimed to analyse blood levels of the neuropeptides substance P (SP), somatostatin (SST), vasoactive intestinal peptide (VIP), calcitonine gene–related peptide (CGRP) and expression of the SP receptor NK-1R in the skin of patients with mastocytosis (n = 46) compared to healthy controls (n = 69). Methods: Substance P, SST, VIP and CGRP plasma levels were analysed by ELISA, serum tryptase levels with the UniCAP System and NK-1R expression in the skin by immunohistochemistry. Results: Plasma levels of SP (P

Durch extremen Zigarettenkonsum bestimmter Tabake konnen GIP-ahnliche („giant cell interstitial pneumonia“) Lungenveranderungen als Sonderform einer Kondensatpneumopathie resultieren, die zur Fallstrickdiagnose einer Sideropneumokoniose oder einer Hartmetalllunge verleiten. Genaue Angaben zur Berufs- und Raucheranamnese insbesondere bzgl. der Herkunft der Zigaretten fuhren zur korrekten Einordnung des Krankheitsbildes.

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.

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.

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).

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.

Inflammatorische fibroide Polypen (IFP) wurden vor 60 Jahren von Vaněk erstmals als „submukoses Granulom mit eosinophiler Infiltration“ beschrieben. IFP stellen polypose Spindelzellproliferate in der Submukosa und Mukosa von Magen, Dunndarm und Kolon mit entzundlicher Infiltration dar. Die Lasion ist bislang als entzundlich-reaktiv angesehen worden. Neuere Daten zeigen, dass die lasionalen Spindelzellen den PDGFRA exprimieren, in der Mehrzahl der Falle sind aktivierende PDGFRA-Mutationen nachweisbar. IFP sind also echte benigne mesenchymale Tumoren des Gastrointestinaltrakts.