胰腺癌.上海.

PANCREATIC NEOPLASMA,PKU.FH 李挺2015年6月，上海,Introduction,These are extremely exciting times for pancreas pathology, the exomes of all of the major tumor types that arise in the pancreas have been sequenced, and each tumor type appears to have a distinct mutational profileEven histologically similar neoplasms of ductal lineage, such as conventional ductal adenocar., mucinous cystic neoplasms, and intraductal papillary mucinous neoplasms, have some distinct genetic features, despite sharing certain key mutations that characterize ductal type,An integration of sequencing with tumor morphology has helped refine the classification of pancreatic neoplasmsA number of the discovered genetic alterations have specific prognostic and in some instances even specific therapeutic implicationsWhile the sequencing tumors of the pancreas continues at break-neck speed, progress has been slower integrating the results of the sequencing into patient care,Infiltrating Ductal Adenocarcinoma,neoplastic glands can be remarkably well-differentiated, and can be difficult to distinguish between reactive non-neoplastic gland and invasive adenocar., despite the highly lethal nature of this cancer （one of the most deadly of all of the solid malignancies）ductal adenocar. elicit an intense desmoplastic reaction, especially within the pancreas itself,Re-endothelialize,SMAD4,18q，肿瘤抑制基因，TGF-B超家族成员，细胞内信号传导inactivated in 55% of IDA, only rarely targeted in other tumor types Immunolabeling for Smad4 accurately reflects gene status. Loss of Smad4 immunoexpression would support a diagnosis of carcinoma rather than reactive atypiaSmad4 loss can also point to a pancreatic primary in a metastasis of unknown origin,In addition, SMAD4 gene status has prognostic significance, with loss of Smad4 being associated with a worse prognosis and more wide spread metastases in patients with ductal adenocar.,Intraductal Neoplasms of the Pancreas,3 types： intraductal papillary mucinous neoplasms (IPMNs) (common, cystic) intraductal tubulopapillary neoplasms (ITPNs) (rare, solid) intraductal tubular pyloric gland-type adenoma,IPMNs,classified based on： macroscopically: main duct-type, branch duct-type grade of dysplasia: Low-, Intermediate-, High-grade cell type: gastric, pancreatobiliary, intestinal, oncocytic,Features of the invasive adenocarcinoma components,The overall incidence of an associated invasive carcinoma in IPMNs is relatively low: branch duct- type IPMNs 15%; main duct type 30%;intestinal type (colloid carcinoma)pancreatobiliary type (tubular-type adenocarcinomas),Mucinous Cystic Neoplasm (MCN),These distinctive neoplasms typically arise in the tail of the pancreas and are much more common in women one of the 3 most common primary cyst-forming neoplasms of the pancreas (IPMN, SCN, MCN) one of the 3 precursors of invasive adenocar. of the pancreas (PanIN, IPMN, MCN),2 components: mucin-producing neoplastic epithelial cells: low-, intermediate-, high-grade characteristic non-neoplastic “ovarian-type” subepithelial stroma,Solid Pseudopapillary Neoplasm (SPN),Uncommon (1-2%), low-grade malignant (10% have malignant behavior) mostly in young womenDespite numerous studies, the histogenesis remains unclear, have not a normal counterpart in the pancreas,Macroscopy,located in any partlarge （mean 7.5cm）highly variable cystic degenerationGrossly well-circumscribed, there is no real fibrous capsule （ neoplastic cells may infiltrate the surrounding pancreatic parenchyma, and even adjacent organs）,Microscopy,cords of monomorphic cells separated by small vessels exhibiting a variable degree of perivascular collagen depositionThe most characteristic feature: pseudo- papillary areas with fibrovascular stalks or rosette-like structures secondary to poor cohesion of the neoplastic cells,neoplastic cells: small and regular with clear or eosinophilic cytoplasm variants: clear cell, pleomorphic, oncocytic Nuclei: uniform, ovoid with finely dispersed chromatin, inconspicuous nucleoli; longitudinal nuclear grooves (characteristic); Rare mitoses,Immunohistochemistry,highly distinctive from other pancreatic neoplasmsThe most sensitive and specific marker is the abnormal intense nuclear expression of beta-catenin, observed in nearly all caseswhich secondary to constitutive activation of Wnt pathway caused by beta-catenin gene (CTNNB1) mutations. There is also a loss or abnormal cytoplasmic expression of E-cadherin,Immunolabeling of SPN with an antibody to beta- catenin. Strong cytoplasmic and nuclear labeling was observed in neoplastic cells (right) as compared with the membranous labeling found in non-neoplastic exocrine cells (left).,The neoplastic cells consistently express vimentin, whereas staining for keratins is typically either negative or only very focal (30%)Other diagnostic markers include CD10, CD99 (dot-like), PR, ER, galectin-3 and alpha-1-antitrypsin,differential diagnosis with neuroendocrine tumors is sometimes difficultsynaptophysin can be focally (31%) or even diffusely (10%) positivechromogranin is consistently negative, as are stains for pancreatic exocrine enzymes such as trypsin and chymotrypsin,Molecular Characteristics,main genetic event (90%) associated to the tumorogenesis of SPN is alteration of the Wnt/beta-catenin (a multifunctional protein with both adhesive and transcriptional activation functions) signaling pathway due to activating point mutations within exon3 of beta-catenin gene (CTNNB1) this can therefore help establish the diagnosis of SPN,Histogenesis,Acinar, ductal, neuroendocrine, and primordial cell origins have been proposed, b