Histopathologists retain a critical role in the diagnosis and management of hepatocellular carcinoma (HCC). HCC arises usually but not exclusively in a background of advanced-stage chronic liver disease. The histological diagnosis of HCC poses many challenges particularly when dealing with liver biopsy specimens due to the heterogeneity of HCC and the difficulty to confirm hepatocellular differentiation in some instances. Primary liver tumors should be considered as a continuum with typical hepatocellular and cholangiocarcinoma at the two ends and a whole range of tumors showing both hepatocellular and cholangiocellular differentiation with or without an associated progenitor/stem cell component in the middle. Characterization of combined (or mixed) hepatocellular-cholangiocarcinoma can be very challenging. In advanced-stage chronic liver disease, the main challenge for the histopathologist is still to differentiate between HCC and its precursors, although this is rarely critical in the clinical setting at present. HCC originating in non-cirrhotic livers needs to be differentiated from other primary and extrahepatic tumors and from hepatocellular adenoma, bearing in mind that progression to malignancy is more through a continuum that watertight histological categories.

Cholangiocarcinoma (CC) is the second most common tumor of the liver, originating from the biliary system with increasing incidence and mortality worldwide. Several new classifications review the significance of tumor localization, site of origin, proliferation and biomarkers in the intrahepatic, perihilar and distal forms of the lesion. Based on growth pattern mass-forming, periductal-infiltrating, intraductal, undefined and mixed types are differentiated. There are further subclassifications which are applied for the histological features, in particular for intrahepatic CC. Recognition of the precursors and early lesions of CC including biliary intraepithelial neoplasia (BilIN), intraductal papillary neoplasm of the bile ducts (IPNB), biliary mucinous cystic neoplasm (MCNB) and the candidate precursors, such as bile duct adenoma and von Meyenburg complex is of increasing significance. In addition to the previously used biliary markers detected by immunohistochemistry, several new markers have been added to the differentiation of both the benign and malignant lesions, which can be used to aid in the subclassification in association with the outcome of CC. Major aspects of biliary carcinogenesis have been revealed, yet, the exact way of this diverse process is still unclear. The factors contributing to molecular cholangiocarcinogenesis include various risk factors, different anatomical localizations, multiple cellular origins, genetic and epigenetic alterations, tumor microenvironment, heterogeneity and clonal evolution. Driver mutations have been identified, implying that they are optimal candidates for targeted therapy. The most promising therapeutic candidates have entered clinical trials.

Chemical carcinogenesis is a multistep process. Genotoxic carcinogens, which are DNA-reactive, induce DNA adduct formation and genetic alterations in target cells, thereby generating mutated cells (initiation). Subsequently, preneoplastic lesions appear through clonal proliferation of the mutated cells and transform into tumors (promotion and progression). Many factors may influence these processes in a dose-dependent manner. Therefore, quantitative analysis plays an important role in studies on the carcinogenic threshold of genotoxic carcinogens. Herein, we present data on the relationship between key carcinogenic events and their deriving point of departure (PoD). Their PoDs were also compared to those of the carcinogenesis pathway. In an experiment, the liver of rats exposed to 2-amino-3,8-dimethylimidazo-(4,5-f)quinoxaline (MeIQx) was examined to determine the formation of MeIQx-DNA adducts, generation of mutations at LacI transgene, and induction of preneoplastic glutathione S-transferase placental form (GST-P)-positive foci and tumors (benign and malignant). The PoDs of the above key events in the carcinogenicity of MeIQx were increased as the carcinogenesis advanced; however, these PoDs were lower than those of tumor induction. Thus, the order of key events during tumor induction in the liver was as follows: formation of DNA adducts < Mutations < GST-positive foci (preneoplasia) < Tumor (adenoma and carcinoma). We also obtained similar data on the genotoxic and carcinogenic PoDs of other hepatocarcinogens, such as 2-amino-3,8-dimethylimidazo(4,5-f)quinoline. These results contribute to elucidating the existence of a genotoxic and carcinogenic threshold.

Deletion of endoplasmic reticulum resident chaperone Grp78 results in activation of the unfolded protein response and causes rapid depletion of the entire intestinal epithelium. Whether modest reduction of Grp78 may affect stem cell fate without compromising intestinal integrity remains unknown. Here, we employ a model of epithelial-specific, heterozygous Grp78 deletion by use of VillinCreERT2-Rosa26ZsGreen/LacZ-Grp78+/fl mice and organoids. We examine models of irradiation and tumorigenesis, both in vitro and in vivo Although we observed no phenotypic changes in Grp78 heterozygous mice, Grp78 heterozygous organoid growth was markedly reduced. Irradiation of Grp78 heterozygous mice resulted in less frequent regeneration of crypts compared with nonrecombined (wild-type) mice, exposing reduced capacity for self-renewal upon genotoxic insult. We crossed mice to Apc-mutant animals for adenoma studies and found that adenomagenesis in Apc heterozygous-Grp78 heterozygous mice was reduced compared with Apc heterozygous controls (1.43 vs. 3.33; P < 0.01). In conclusion, epithelium-specific Grp78 heterozygosity compromises epithelial fitness under conditions requiring expansive growth such as adenomagenesis or regeneration after γ-irradiation. These results suggest that Grp78 may be a therapeutic target in prevention of intestinal neoplasms without affecting normal tissue.Significance: Heterozygous disruption of chaperone protein Grp78 reduces tissue regeneration and expansive growth and protects from tumor formation without affecting intestinal homeostasis. Cancer Res; 78(21); 6098-106. ©2018 AACR.

Due to the cytotoxic effects of old chemotherapy regimens used in the islet cell tumors, capecitabine plus temozolomide combination has now become the first choice in the treatment of malignant insulinoma (MIoma). We present this case to emphasize and remind that a durable complete response in advanced stage MIoma may be achieved with a short course of streptozotocin plus doxorubicin combination.