Serratierte Läsionen im Kolorektum – ein pathologisches Problem oder ein Problem der Pathologen?

Serratierte Läsionen im Kolorektum stellen eine Problemzone für Kliniker und Pathologen dar; dies liegt zum einen an der noch nicht allgemein bekannten Nomenklatur, zum anderen an dem noch nicht abschließend geklärten Progressionsrisiko der verschiedenen serratierten Polypen. Mittlerweile gilt als akzeptiert, dass neben der klassischen Adenom-Karzinom-Sequenz ein alternativer serratierter und ein sogenannter gemischter Karzinogeneseweg existiert; diese Karzinogenesewege sind in Bezug auf die präinvasiven Vorstufen, die molekularen Pfade und die Prognose der Karzinome heterogen. Bei den serratierten Adenokarzinomen lassen sich ein Niedrigrisiko-Subtyp (Häufigkeit 70%) sowie ein Hochrisiko-Subtyp (Häufigkeit >80%, mit meist distaler Lokalisation, dem traditionellen serratierten Adenom als Vorläuferläsion, KRAS-Mutation, niedriger Mikrosatelliteninstabilität/mikrosatellitenstabil, CpG-Methylierung/ p53-Akkumulation und einer 5-Jahres-Überlebens-Rate von 70%) and a high-risk subtype (frequency >80%, often with distal location, the traditional serrated adenoma as a precursor lesion, KRAS mutation, low microsatellite instability/microsatellite stable, CpG methylation/ p53 accumulation and a 5-year survival rate of <30%). The evaluation of the microsatellite status as well as the detection of BRAF or KRAS mutations together with immunohistochemistry for hMLH1 and p53 will allow a discrimination between these two subtypes and will become increasingly important in the future.Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich

The G Protein-Coupled Receptor RAI3 Is an Independent Prognostic Factor for Pancreatic Cancer Survival and Regulates Proliferation via STAT3 Phosphorylation

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest tumors worldwide. Understanding the function of gene expression alterations is a prerequisite for developing new strategies in diagnostic and therapy. GPRC5A (RAI3), coding for a seven transmembrane G protein-coupled receptor is known to be overexpressed in pancreatic cancer and might be an interesting candidate for therapeutic intervention. Expression levels of RAI3 were compared using a tissue microarray of 435 resected patients with pancreatic cancer as well as 209 samples from chronic pancreatitis (CP), intra-ductal papillary mucinous neoplasm (IPMN) and normal pancreatic tissue. To elucidate the function of RAI3 overexpression, siRNA based knock-down was used and transfected cells were analyzed using proliferation and migration assays. Pancreatic cancer patients showed a statistically significant overexpression of RAI3 in comparison to normal and chronic pancreatitis tissue. Especially the loss of apical RAI3 expression represents an independent prognostic parameter for overall survival of patients with pancreatic cancer. Suppression of GPRC5a results in decreased cell growth, proliferation and migration in pancreatic cancer cell lines via a STAT3 modulated pathway, independent from ERK activation

Matrix-comparative genomic hybridization from multicenter formalin-fixed paraffin-embedded colorectal cancer tissue blocks

<p>Abstract</p> <p>Background</p> <p>The identification of genomic signatures of colorectal cancer for risk stratification requires the study of large series of cancer patients with an extensive clinical follow-up. Multicentric clinical studies represent an ideal source of well documented archived material for this type of analyses.</p> <p>Methods</p> <p>To verify if this material is technically suitable to perform matrix-CGH, we performed a pilot study using macrodissected 29 formalin-fixed, paraffin-embedded tissue samples collected within the framework of the EORTC-GI/PETACC-2 trial for colorectal cancer. The scientific aim was to identify prognostic genomic signatures differentiating locally restricted (UICC stages II-III) from systemically advanced (UICC stage IV) colorectal tumours.</p> <p>Results</p> <p>The majority of archived tissue samples collected in the different centers was suitable to perform matrix-CGH. 5/7 advanced tumours displayed 13q-gain and 18q-loss. In locally restricted tumours, only 6/12 tumours showed a gain on 13q and 7/12 tumours showed a loss on 18q. Interphase-FISH and high-resolution array-mapping of the gain on 13q confirmed the validity of the array-data and narrowed the chromosomal interval containing potential oncogenes.</p> <p>Conclusion</p> <p>Archival, paraffin-embedded tissue samples collected in multicentric clinical trials are suitable for matrix-CGH analyses and allow the identification of prognostic signatures and aberrations harbouring potential new oncogenes.</p

Ampullary cancers harbor ELF3 tumor suppressor gene mutations and exhibit frequent WNT dysregulation

The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of β-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis

Expert Opinion on Laparoscopic Surgery for Colorectal Cancer Parallels Evidence from a Cumulative Meta-Analysis of Randomized Controlled Trials

PMID: 22532846 [PubMed - indexed for MEDLINE] PMCID: PMC3332109 Free PMC ArticlePeer reviewedPublisher PD

Ampullary Cancers Harbor ELF3 Tumor Suppressor Gene Mutations and Exhibit Frequent WNT Dysregulation

The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of beta-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis

Precursor Lesions for Sporadic Pancreatic Cancer: PanIN, IPMN, and MCN

Pancreatic cancer is still a dismal disease. The high mortality rate is mainly caused by the lack of highly sensitive and specific diagnostic tools, and most of the patients are diagnosed in an advanced and incurable stage. Knowledge about precursor lesions for pancreatic cancer has grown significantly over the last decade, and nowadays we know that mainly three lesions (PanIN, and IPMN, MCN) are responsible for the development of pancreatic cancer. The early detection of these lesions is still challenging but provides the chance to cure patients before they might get an invasive pancreatic carcinoma. This paper focuses on PanIN, IPMN, and MCN lesions and reviews the current level of knowledge and clinical measures

Altered Distribution of -Catenin, and Its Binding

pression was more closely linked to E-cadherin alterations in UC-related cancers than in sporadic cancers. In contrast, abnormal #-catenin expression was more closely linked to APC alterations in sporadic cancers than in UCrelated cancers. These data suggest that alterations of the #-catenin pathway are important in both UC-related and sporadic colorectal cancers. However, differences in the expression patterns of #-catenin, E-cadherin, and APC between UCrelated and sporadic colorectal cancers suggest that the specific alterations in this pathway may differ in these two cancer groups. KEY WORDS: APC, #-catenin, Colorectal cancer, E-cadherin, Immunohistochemistry, Ulcerative colitis. Mod Pathol 2001;14(1):29--39 #-catenin is a multifunctional protein that is involved in cell-- cell interaction and transcriptional signaling (1--5). #-catenin expression is largely regulated by its two major binding partners, E-cadherin on the membrane and the adenomatous polyposis coli (APC) protein i