Verhandlungen der Deutschen Gesellschaft fur Pathologie最新文献

The intraductal papillary-mucinous neoplasms of the pancreas have only recently been recognized as a clinical and pathological entity. They show an adenoma-carcinoma sequence, but have a much more favorable prognosis than ductal adenocarcinoma. Moreover, it has become clear that they constitute a heterogeneous group with at least four histopathological subtypes that have different biological properties with different prognostic implications.

Lynch syndrome (formerly called hereditary nonpolyposis colorectal cancer) is a hereditary syndrome resulting in a high risk for colorectal cancer at young age. About 2-3% of all colorectal cancers arise in the setting of Lynch syndrome and the tumors are characterized by microsatellite instabillity (MSI)due to a mutation in one of the mismatch repair genes. Of sporadic colorectal cancer about 15 % have MSI too, but due to hypermethylation of the promotor of the MHL1 gene. Recognizing Lynch syndrome is important, since patients and their families need to undergo a screening program. Based on clinical (colorectal cancer in patients younger than 50 years, or multiple colorectal cancer in one patient) and pathological (mucinous carcinoma, intraepithelial lymphocytes) features pathologists are increasingly able to recognize cases of colorectal cancer that are associated with Lynch syndrome. We propose a cost-effective and ethically correct approach for detecting Lynch syndrome by pathologists.

Thyroid carcinoma has been traditionally subdivided into the four major groups papillary, follicular, medullary, and anaplastic carcinoma. The WHO classification of thyroid tumours, published in 2004, has added to these four tumour groups the entity of poorly differentiated carcinoma as well as a broad variety of rare thyroid malignancies. Another important change concerns the histological hallmarks of papillary carcinoma, the diagnosis of which is now exclusively dependent on characteristic nuclear features. The aim of the present paper is to highlight diagnostic problems particularly caused by the alteration introduced onto the WHO classification, This includes a proposal of a more systematic thyroid carcinoma classification based on the histogenetic differentiation (follicular cell differentiation. C cell differentiation, rare carcinomas) and tumour grading of carcinomas with follicular cell differentiation (differentiated, poorly differentiated and anaplastic carcinomas) as well as commentaries on the diagnosis of papillary carcinoma, poorly differentiated carcinoma, and rare types of thyroid carcinoma (squamous cell carcinoma, mucoepidermoid carcinoma, sclerosing mucoepidermoid carcinoma with eosinophilia, mucinous carcinoma, SETTLE, and CASTLE).

Purpose: Although TP53 is one of the most studied genes/proteins in ovarian carcinomas, the predictive value of TP53 alterations is still ambiguous.

Experimental design: We performed analyses of the TP53 mutational status and its protein expression by immunohistochemistry. Moreover, the single nucleotide polymorphism SNP309 in the P2-promotor of the HDM2 gene was investigated. We correlated the results with the age of onset and the outcome of 107 ovarian carcinoma patients.

Results: In our study, we identified a large group of patients with TP53 overexpression despite having a wild-type gene (49% of all patients with wild-type TP53). This was associated with a significantly shortened overall survival time (p = 0.019). Patients with TP53 alterations (especially those with overexpression of wild-type TP53) were also more refractory to chemotherapy than patients with normal TP53 (p = 0.027). The Gallele of the SNP309 is associated with an earlier age of onset in estrogen receptor expressing FIGO stage III patients (p = 0.048). In contrast, in FIGO III patients, a weakened TP53 pathway (either G-allele of SNP309 or a TP53 mutation) is correlated with an increased overall survival compared with patients whose tumors are wild-type for TP53 and SNP309 (p = 0.0035).

Conclusion: Our study provides evidence that both germ line and somatic alterations of the TP53 pathway influence incidence and survival of ovarian carcinoma, and it underscores the importance of assessing the functionality of TP53 in order to predict sensitivity of platin-based chemotherapies and patient outcome.

More than 40 years ago Morson (1962) coined the paradigm that adenomas are the main precursors of colorectal carcinoma (CRC) whereas hyperplastic polyps are "non-neoplastic" lesions without cancer risk. Later-on (1988) this was supported by Vogelstein's molecular adenoma-carcinoma progression model with APC mutations being a key-initiating molecular event (classic adenoma-carcinoma pathway). In 1992 a new molecular mechanism, the mutator pathway of CRC was discovered in HNPCC patients. Deficiencies in mismatch repair (MMR-) gene function (mainly of MSH2 and MLH1) cause microsatellite instability (MSI) in about 15% of CRC. It's the merit of Jass (1999) to demonstrate that carcinogenesis in sporadic MSI-positive CRC is associated with serrated polyps. These polyps form the hallmark of a third "serrated (neoplasia) pathway" exhibiting a hyperplastic polyp-like morphology characterized by serrated crypt epithelium. In contrast to adenomatous polyps with readily apparent cytological atypia (dysplasia) the feature of dysplasia in serrated polyps is architectural distortion. Today four categories of serrated lesions can be delineated: (i) the most frequent classic hyperplastic polyp (HP, 80-90%), followed by (ii) sessile serrated adenoma (SSA, 15-20%) and (iii) by the rare traditional serrated adenoma (TSA, < 1%). Whereas HPP are benign, SSA are probably slowly progressing lesions and TSA as well as SSA with APC-type adenomatous atypias (iv. mixed SSA) indicate increased cancer risk. Molecularly serrated polyps seem to share a defect in apoptosis caused by either K-ras or BRAF gene mutation leading to CpG island methylation (CIMP) affecting MLHI (--> MSI type CRC) or non-MMR oncogenes (--> MSI-L or MSS type serrated CRC, Mäkinen 2007).

PEA-15 (Phosphoprotein enriched in astrocytes 15 kD) is a death effector domain-containing protein, which is involved in the regulation of apoptotic cell death. Since PEA-15 is highly expressed in cells of glial origin, we studied the role of PEA-15 in human malignant brain tumors. Immunohistochemical analysis of PEA-15 expression shows strong immunoreactivity in astrocytomas and glioblastomas. Phosphorylation of PEA-15 at Ser116 is found in vivo in perinecrotic areas in glioblastomas and in vitro after glucose deprivation of glioblastoma cells. Overexpression of PEA-15 induces a marked resistance against glucose deprivation-induced apoptosis, whereas siRNA-mediated down-regulation of endogenous PEA-15 results in the sensitization to glucose withdrawal-mediated cell death. This anti-apoptotic activity of PEA-15 under low glucose conditions depends on its phosphorylation at Ser116 Moreover, siRNA-mediated knockdown of PEA-15 abolishes the tumorigenicity of U87MG glioblastoma cells in vivo. PEA-15 regulates the level of phosphorylated ERK1/2 in glioblastoma cells and the PEA-15-dependent protection from glucose deprivation-induced cell death requires ERK1/2 signaling. PEA-15 transcriptionally up-regulates the glucose transporter 3, which is abrogated by the inhibition of ERK1/2 phosphorylation. Taken together, our findings suggest that Ser116-phosphorylated PEA-15 renders glioma cells resistant to glucose deprivation-mediated cell death as encountered in poor microenvironments, e.g. in perinecrotic areas of glioblastomas.

Unlabelled: 50-70% of patients with malignant thymic epithelial tumors (thymomas or thymic carcinomas) cannot be cured by current treatment strategies and are therefore candidates for second line therapies.

Methods: Malignant thymomas and thymic squamous cell carcinomas (TSCC) were analyzed by genomic sequencing and functional tests using ex vivo explant cell cultures to study alterations of the receptor tyrosine kinases c-Kit and epidermal growth factor receptor (EGFR) and their relevance for tumor cell function.

Results: Overexpression of c-Kit was observed only in TSCC, but not in thymomas. In spite of overexpression in almost 90% of TSCC, c-Kit mutations were very infrequent (10%). A strong expression of the EGFR was observed in 70% of thymomas and 35% of TSCC. Mutations of exons encoding extra- or intracellular domains were not observed in a single case (n=40). However, in vitro studies with epithelial explant cell cultures of these tumors suggested that treatment with Cetuximab was effective in a subset of cases, while others were resistant.

Conclusions: Our findings may forecast therapeutic responses to emerging target treatments in malignant thymomas and thymic carcinomas and may help to develop novel strategies.

Lobular carcinoma in situ (LCIS) of the breast typically is an incidental finding in breast biopsies performed for a variety of reasons. As patients with LCIS have a bilaterally increased risk of developing invasive ductal or lobular breast cancer, the lesion is presently considered an indicator rather than a direct precursor of breast cancer. However, this view is challenged by the finding that LCIS often accompanies invasive lobular carcinomas (ILC) and that the frequency of ILC following LCIS is far higher compared to unselected patients. To further examine the role of LCIS in the development of invasive breast cancer, we analysed a series of patients with pure LCIS, who later developed invasive breast cancer. Mitochondrial D-loop sequencing revealed a clonal relationship of LCIS and a subset of ILC occurring in the same breast between 2 and 10 years later. Apparently, LCIS has a chimeric role in breast cancer development and is not only a risk factor but in some cases a precursor of ILC.

SIAH-1 (seven in absentia homologue-1) is an E3-ubiquitin ligase that facilitates labelling and subsequent proteasomal degradation of different proteins like transcription factors (e.g. c-myb) and coactivators (e.g. beta-catenin). Here we show that SIAH-1 expression is frequently reduced in human hepatocarcinogenesis. However, further reduction of SIAH-1 bioavailability by gene-specific siRNA (RNAinterference) in HCC cell lines resulted in significantly decreased tumor cell viability. Therefore we conclude that distinct SIAH-1 levels mediate pro-tumorigenic effects in HCC cells and that further SIAH-1 inhibition may represent a new therapeutic strategy in the treatment of human hepatocellular carcinoma.

Ulcerative colitis (UC)-related intraepithelial neoplasia and its distinction from regenerative changes and sporadic adenomas occurring in UC is one of the greatest challenges in gastrointestinal pathology. Recently, the molecular changes in UC-related neoplastic progression have been determined and compared with the molecular changes in sporadic carcinogenesis. Diagnostically promising differences between sporadic and UC-related carcinogenesis are the advent of genetic changes in non-neoplastic UC-related mucosa and the early loss of 18q (harbouring SMAD2, SMAD4, and DCC) and 17p (site of p53) in UC-related tumorigenesis. These studies have given rise to a number of adjunct methods in the determination of UC-related neoplasia. Never the less, conventional histopathology still remains the gold standard in the diagnosis of UC-related neoplasia. Training of histopathologists therefore is one of the most important issues in conquering the diagnostic challenges of UC-related neoplasia. The working group "Gastrointestinal Pathology" of the German Society for Pathology set up a diagnostic multicenter trial which was open to everyone interested. The interobserver variability regarding ulcerative colitis-related neoplasia was quite promising (kappa = 0.63). A consensus diagnosis was reached for all the specimens and diagnostic criteria for UC-related neoplasia were discussed, reevaluated, and agreed on. Adjunct methods and emerging markers for the diagnosis of ulcerative colitis-related neoplasia (p53, Ki67, AMACR) and its distinction from regenerative changes and sporadic adenomas occurring in UC (ALM) will be presented and discussed.