Christian Sauer

MYC High Level Gene Amplification Is a Distinctive Feature of Angiosarcomas after Irradiation or Chronic Lymphedema

Angiosarcomas (AS) are rare vascular malignancies that arise either de novo as primary tumors or secondary to irradiation or chronic lymphedema. The cytogenetics of angiosarcomas are poorly characterized. We applied array-comparative genomic hybridization as a screening method to identify recurrent alterations in 22 cases. Recurrent genetic alterations were identified only in secondary but not in primary AS. The most frequent recurrent alterations were high level amplifications on chromosome 8q24.21 (50%), followed by 10p12.33 (33%) and 5q35.3 (11%). Fluorescence in situ hybridization analysis in 28 primary and 33 secondary angiosarcomas (31 tumors secondary to irradiation, 2 tumors secondary to chronic lymphedema) confirmed high level amplification of MYC on chromosome 8q24.21 as a recurrent genetic alteration found exclusively in 55% of AS secondary to irradiation or chronic lymphedema, but not in primary AS. Amplification of MYC did not predispose to high grade morphology or increased cell turnover. In conclusion, despite their identical morphology, secondary AS are genetically different from primary AS and are characterized by a high frequency of high level amplifications of MYC. This finding may have implications both for the diagnosis and treatment of these tumors.

Expression and activity of matrix metalloproteinases-2 and -9 in serum, core needle biopsies and tissue specimens of prostate cancer patients

Prostate cancer is the most common cancer in men and second in the cancer-related frequency of mortality. Matrix metalloproteinases (MMPs) are involved in tumor invasion and metastasis in various malignancies. MMP-2 and MMP-9 are capable of digesting collagen type IV. Numerous studies have demonstrated an association between increased MMP-2 and -9 expression and tumor progression in various tumors. In this study, the expression and activities of MMP-2 and -9 were assessed in serum probes and tumor tissue from core needle biopsies and radical prostatectomies of 97 patients. MMP-2 and -9 serum expression was analyzed in a subgroup of 31 patients. MMP-9 serum expression was significantly increased in tumor patients and correlated with tumor grade. In contrast, the MMP-9 tissue expression and activity revealed no significant correlations to tumor stage or grade. The MMP-2 activity, however, showed a positive correlation for MMP-2 with tumor stage. Increased activity was predominantly detected in advanced tumor stages. Immunohistochemical analysis of MMP-2 expression demonstrated a positive association with tumor grade in prostatectomy specimens. The relative expression rates in biopsies matched in 65% with those of the prostatectomies. Detection of MMP-2 in core needle biopsies seems not to be a helpful marker for diagnostic purposes.

Desmosomal Plakophilins in the Prostate and Prostatic Adenocarcinomas: Implications for Diagnosis and Tumor Progression

The plakophilins, members of the armadillo-repeat family, consist of three different proteins (PKP1-3) that are specifically recruited to desmosomal plaques in a highly cell type-specific manner. Using immunofluorescence, immunoelectron microscopy, and immunoblot, we found that all three plakophilins occurred in luminal and basal cells of the pseudostratified prostate epithelium. The analysis of 135 cases of prostatic adenocarcinomas grouped into tumors with low (Gleason score < or = 6), intermediate (Gleason score 7), and high Gleason score (8 < or = Gleason score < or = 10) showed that the expression of PKP1 was reduced or lost in adenocarcinomas with high Gleason scores. The expression of PKP2 was unchanged in all prostatic adenocarcinomas analyzed. In contrast, PKP3 expression was increased in carcinomas with high Gleason scores in comparison with carcinomas with low Gleason scores. In DU 145 cell lines with either overexpression or knockdown of PKP3, both imbalances resulted in fewer desmosomal cell contacts. In addition, overexpression of PKP3 in DU 145 cells led to an augmentation in proliferation rate. Our data imply that both loss of PKP1 and up-regulation of PKP3 expression are biologically important events in prostate cancer and are associated with a more aggressive phenotype.

Case report: Intraductal tubulopapillary neoplasm of the pancreas with unique clear cell phenotype.

Intraductal tubulopapillary neoplasms of the pancreas are very rare tumors characterized by intraductal tubulopapillary growth, ductal differentiation, scant intracellular mucin production and cellular dysplasia. Here, we report the first case of an intraductal tubulopapillary neoplasm of the pancreas with clear cell morphology. The tumor was detected during the diagnostic work-up of acute pancreatitis in a 43- year old female. Histological examination revealed a tumor with the typical architecture of an intraductal tubulopapillary neoplasm of the pancreas with tumor cells showing abundant clear cytoplasm and Di-PAS negativity. Immunohistochemistry revealed positivity for Pan-CK, CK7, CK8/18, MUC1, MUC6, carbonic anhydrase IX, CD10, EMA, β-catenin and e-cadherin. Sanger sequencing did not detect mutations for β-catenin, BRAF, KRAS, PIK3CA and GNAS. Altogether, histology, immunohistochemical expression profile (MUC1+, MUC6+, MUC2-, MUC5AC-, thrypsin-, chymotrypsin-, CDX2-) and sequencing results led to the diagnosis of intraductal tubulopapillary neoplasm. However, the neoplasm consisted of cells showing abundant clear cytoplasm, a morphological pattern not being described so far in the current classification of pancreatic intraductal neoplasms. Potential differential diagnosis and the molecular basis of clear cell morphology are discussed. In conclusion, we consider this tumor as intraductal tubulopapillary neoplasm of the pancreas with unique clear cell phenotype. After surgery and without adjuvant therapy, the patient’s clinical course has been uneventful for over two years now.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1051828790117127

High frequency of MYC gene amplification is a common feature of radiation‐induced sarcomas. Further results from EORTC STBSG TL 01/01

Irradiation is a major causative factor among the small subgroup of sarcomas with a known etiology. The prognosis of radiation‐induced sarcomas (RIS) is significantly worse than that of their spontaneous counterparts. The most frequent histological subtypes include undifferentiated pleomorphic sarcomas, angiosarcomas, and leiomyosarcomas. A high frequency of MYC amplifications in radiation‐induced angiosarcomas, but not in primary angiosarcomas, has recently been described. To investigate whether MYC amplifications are also frequent in RIS other than angiosarcomas, we analyzed the MYC amplification status of 83 RIS and 192 sporadic sarcomas by fluorescence in situ hybridization. We found significantly higher numbers of MYC amplifications in RIS than in sporadic sarcomas (P < 0.0001), especially in angiosarcomas, undifferentiated pleomorphic sarcomas, and leiomyosarcomas. Angiosarcomas were special in that MYC amplifications were particularly frequent and always high level, while other RIS showed low‐level amplifications. We conclude that MYC amplifications are a frequent feature of RIS as a group and may contribute to the biology of these tumors.

Relaxed imprinting of IGF2 in peripheral blood cells of patients with a history of prostate cancer

Background Insulin-like growth factor 2 (IGF2) is the predominant IGF in adults and regulates cell growth. In contrast to normal tissues, where IGF2 is imprinted and only expressed from the paternal allele, loss of imprinting (LOI) and biallelic IGF2 expression are observed in many cancers including prostate cancer (PCa). We here studied whether LOI of IGF2 in normal circulating peripheral blood lymphocytes can predict increased PCa risk. Samples and methods We analyzed IGF2 protein levels, IGF2 820G/A genotype and imprinting status, as well as methylation status of the IGF2 imprinting control region (ICR) in 113 blood samples of patients with a history of radical prostatectomy (RPE) for PCa by ELISA, restriction-fragment length polymorphism, and bisulfite-DNA sequencing. Results were compared to 249 male blood donors with unknown prostate specific antigen (PSA) status. Results The 820G/A genotype was enriched in the RPE group and was associated with younger age at cancer diagnosis. LOI in patients was only slightly more frequent than in controls, but IGF2 levels were significantly higher and uncoupled from the imprinting status. Analysis of the IGF2/H19 ICR revealed marked hypermethylation. Conclusions The IGF 820G/A genotype is associated with PCa diagnosis at younger age. Increased IGF2 in patients with PCa appears to be the result of impaired imprinting in non-neoplastic cells rather than a paracrine tumor product. Uncoupling of IGF2 protein levels from imprinting status (not LOI alone) and hypermethylation of the ICR characterized PCa patients and could have the potential to indicate persons at risk in screening programs.

Carcinoma of the colon and rectum with deregulation of insulin-like growth factor 2 signaling: clinical and molecular implications

AbstractBackgroundLoss of imprinting (LOI) of the insulin-like growth factor 2 (IGF2) is an early event in the development of colorectal cancer (CRC). nWhether LOI of IGF2 denotes a molecular or clinical cancer subgroup is currently unknown.MethodsTumor biopsies and paired normal mucosa from 399 patients with extensive clinical annotations were analyzed for LOI and IGF2 expression. LOI status in 140 informative cases was correlated with clinicopathologic parameters and outcome.ResultsLOI was frequent in normal mucosa and tumors and occurred throughout the large intestine. LOI was unrelated to microsatellite instability, KRAS mutation status, stage, and survival. However, CRC with LOI showed increased IGF2 protein levels and activation of AKT1. Gene expression analysis of tumors with and without LOI and knockdown of IGF2 in cell lines revealed that IGF2 induced distinct sets of activated and repressed genes, including Wnt5a, CEACAM6, IGF2BP3, KPN2A, BRCA2, and CDK1. Inhibition of AKT1 in IGF2-stimulated cells showed that the downstream effects of IGF2 on cell proliferation and gene expression were strictly AKT1-dependent.ConclusionsLOI of IGF2 is a frequent and early event in CRC that occurs both in the adenomatous polyposis coli (APC) gene-mutated and serrated route of carcinogenesis. LOI leads to overexpression of IGF2, activates IGF1R and AKT1, and is a powerful driver of cell proliferation. Moreover, our results suggest that IGF2 via AKT1 also contributes to non-canonical wnt signaling. Although LOI had no significant impact on major clinical parameters and outcome, its potential as a target for preventive and therapeutic interventions merits further investigation.n

[Regressive changes after short-term neoadjuvant antihormonal therapy in prostatic carcinoma: the value of Gleason grading].

ZusammenfassungTrotz einer fehlenden Verbesserung des Langzeitüberlebens werden einige Patienten mit Prostatakarzinomen vor einer radikalen Prostatektomie kurzzeitig antihormonell vorbehandelt. Wir haben erstmals den Einfluss einer kurzzeitigen neoadjuvanten Hormontherapie auf das Gleason-Grading untersucht.Die häufigsten Veränderungen bei 82 kurzzeitig vorbehandelten Tumoren wurden anhand eines Scores ermittelt und quantifiziert. Die Ergebnisse wurden mit Kontrolltumoren ohne Vorbehandlung und den präoperativen Nadelbiopsaten verglichen.In den ersten 4xa0Wochen fand sich die stärkste Zunahme der Regression, danach stellte sich ein kurvenförmiger Verlauf ein. In den ersten 2xa0Wochen hingegen waren die Veränderungen gegenüber dem Kontrollgewebe nicht unterschiedlich. Im Vergleich mit den Nadelbiopsien zeigte sich, dass bei den therapierten Tumoren nach der 2. Woche eine häufigere Übergraduierung im Gegensatz zu den Kontrolltumoren zu finden war.Nach der 2. Behandlungswoche einer neoadjuvanten antihormonellen Therapie sind die regressiven Veränderungen bereits derart ausgeprägt, dass ein Grading nach Gleason nicht mehr empfohlen werden kann.AbstractAlthough neodjuvant, antihormonal therapy does not lead to an improvement in the outcome of prostatic carcinoma it is still used in the short-term in a subset of patients. Here we report the regressive changes due to this short-term treatment and analyse the impact on Gleason grading. The most frequent regressive changes in 82 tumors treated short-term were determined and quantified. The results were compared to a matched control group and also to the preoperative needle biopsies.A steep increase in regressive changes was observed within the first 4xa0weeks. After this point, changes increased only mildly. Within the first 2xa0weeks of treatment no significant changes compared to control tissue were present. Compared to the preoperative needle biopsies, pretreated tumors showed a significant upgrading. After 2xa0weeks of neoadjuvant antihormonal therapy, regressive changes are so great, that Gleason grading can no longer be recommended.

Margin status of the vas deferens in radical prostatectomy specimens: relevant or waste of time?

Positive surgical margins (PSM) after radical prostatectomy are of great interest, but investigation of the vas deferens (VD) is not recommended. This study examined the VD margins in radical prostatectomy patients to report the incidence of PSM and their clinical staging.

Follicular erythematous papules with keratotic spicules: a quiz. Trichodysplasia spinulosa.

A 63-year-old man presented with an asymptomatic “rash” that had started on the face 6 months ago and subsequently extended to the trunk and the arms. A few days before consultation at our department, he had been admitted to the Department of Haemato-Oncology due to unclear anaemia. Laboratory workup, serum electrophoresis and bone marrow biopsy had revealed multiple myeloma type IgG kappa stage III according to the Durie-Salmon staging system. The Follicular Erythematous Papules with Keratotic Spicules: A Quiz