Background
Making the distinction between primary mucinous and metastatic ovarian tumors is often difficult, especially in tumors with a primary source from the gastrointestinal tract, pancreas and biliary tree. The aim of the following paper is to provide an overview of the problematics, with a focus on the possibilities of the differential diagnosis at the macroscopic, microscopic and immunohistochemical level.
Main body
The three main aspects of mucinous ovarian tumors are described in detail, including the comparison of the available diagnostic algorithms based on the evaluation of mostly macroscopic features, characterization of the spectrum of microscopic features, and a detailed analysis of the immunophenotype comparing 20 antibodies with the assessment of their statistical significance for differential diagnosis purposes. Specific features, including Krukenberg tumor and pseudomyxoma peritonei, are also discussed.
Conclusion
Despite the growing knowledge of the macroscopic and microscopic features of ovarian mucinous tumors and the availability of a wide range of immunohistochemical antibodies useful in this setting, there still remains a group of tumors which cannot be precisely classified without close clinical-pathological cooperation.
Nonalcoholic fatty liver disease is the most common chronic liver disease and may progress to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). The molecular determinants of this pathogenic progression, however, remain largely undefined. Since liver tumorigenesis is driven by apoptosis, we examined the effect of overt hepatocyte apoptosis in a mouse model of NASH using mice lacking myeloid cell leukemia 1 (Mcl1), a pro-survival member of the BCL-2 protein family. Hepatocyte-specific Mcl1 knockout (Mcl1 Δhep) mice and control littermates were fed chow or FFC (high saturated fat, fructose, and cholesterol) diet, which induces NASH, for 4 and 10 months. Thereafter, liver injury, inflammation, fibrosis, and tumor development were evaluated biochemically and histologically. Mcl1 Δhep mice fed with the FFC diet for 4 months displayed a marked increase in liver injury, hepatocyte apoptosis, hepatocyte proliferation, macrophage-associated liver inflammation, and pericellular fibrosis in contrast to chow-fed Mcl1 Δhep and FFC diet-fed Mcl1-expressing littermates. After 10 months of feeding, 78% of FFC diet-fed Mcl1 Δhep mice developed liver tumors compared to 38% of chow-fed mice of the same genotype. Tumors in FFC dietfed Mcl1 Δhep mice were characterized by cytologic atypia, altered liver architecture, immunopositivity for glutamine synthetase, and histologically qualified as HCC. In conclusion, this study provides evidence that excessive hepatocyte apoptosis exacerbates the NASH phenotype with enhancement of tumorigenesis in mice.
Activation of the endoplasmic reticulum stress sensor PERK is a feature of nonalcoholic steatohepatitis (NASH), yet regulators of PERK signaling remain undefined in this context. P58IPK regulates PERK; however, its role in NASH has not been examined. Aim: the aim of this study was to assess the in vivo role of p58IPK in the pathogenesis of dietary NASH. Methods: parameters of hepatocyte cell death, liver injury, inflammation, fibrosis, indirect calorimetry and PERK activation were assessed in p58IPK knockout (p58ipk−/−) mice and their wildtype littermate controls fed a diet enriched in Fat, Fructose, and Cholesterol (FFC) for 20 weeks. Results: PERK activation was attenuated in FFC-fed p58ipk−/− mice. Accordingly, FFC-fed p58ipk−/− mice demonstrated a reduction in hepatocyte apoptosis and death receptor expression, with a significant reduction in serum alanine transaminase values. Correspondingly, macrophage accumulation and fibrosis were significantly lower in FFC-fed p58ipk−/− mice. Conclusion: we have demonstrated that in an in vivo dietary NASH model p58IPK mediates hepatocyte apoptosis and liver injury, likely via PERK phosphorylation. In the absence of p58IPK, PERK phosphorylation and NASH are attenuated. Inhibition of hepatic p58IPK may be a future target for NASH therapy.
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