Smad4 restricts injury-provoked biliary proliferation and carcinogenesis.

Cholangiocarcinoma (CCA) is a deadly and heterogeneous type of cancer characterized by a spectrum of epidemiologic associations as well as genetic and epigenetic alterations. We seek to understand how these features inter-relate in the earliest phase of cancer development and through the course of disease progression. For this, we studied murine models of liver injury integrating the most commonly occurring gene mutations of CCA - including Kras, Tp53, Arid1a and Smad4 - as well as murine hepatobiliary cancer models and derived primary cell lines based on these mutations. Among commonly mutated genes in CCA, we found that Smad4 functions uniquely to restrict reactive cholangiocyte expansion to liver injury through restraint of the proliferative response. Inactivation of Smad4 accelerates carcinogenesis, provoking pre-neoplastic biliary lesions and CCA development in an injury setting. Expression analyses of Smad4-perturbed reactive cholangiocytes and CCA lines demonstrated shared enriched pathways, including cell-cycle regulation, MYC signaling and oxidative phosphorylation, suggesting that Smad4 may act via these mechanisms to regulate cholangiocyte proliferation and progression to CCA. Overall, we showed that TGFß/SMAD4 signaling serves as a critical barrier restraining cholangiocyte expansion and malignant transformation in states of biliary injury.

Leiomyomas beyond the uterus: unusual locations, rare manifestations.

Uterine leiomyomas affect 20%-30% of women older than 35 years. Extrauterine leiomyomas are rarer, and they present a greater diagnostic challenge: These histologically benign tumors, which originate from smooth muscle cells, usually arise in the genitourinary tract (in the vulva, ovaries, urethra, and urinary bladder) but may arise in nearly any anatomic site. In addition, unusual growth patterns may be seen, including benign metastasizing leiomyoma, disseminated peritoneal leiomyomatosis, intravenous leiomyomatosis, parasitic leiomyoma, and retroperitoneal growth. In the presence of such a pattern, a synchronous uterine leiomyoma or a previous hysterectomy for removal of a primary uterine tumor may be indicative of the diagnosis. However, some extrauterine leiomyomas may mimic malignancies, and serious diagnostic errors may result. The most useful modalities for detecting extrauterine leiomyomas are ultrasonography, computed tomography, and magnetic resonance (MR) imaging. The superb contrast resolution and multiplanar capabilities of MR imaging make it particularly valuable for characterizing these tumors, which usually show low signal intensity similar to that of smooth muscle on T2-weighted images. The radiologist's recognition of this and other characteristic features may help steer the clinician toward timely, appropriate management and away from unnecessary, potentially harmful treatment.

Kras and Tp53 Mutations Cause Cholangiocyte- and Hepatocyte-Derived Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (iCCA) is a primary liver cancer epidemiologically linked with liver injury, which has poorly understood incipient stages and lacks early diagnostics and effective therapies. While iCCA is conventionally thought to arise from the biliary tract, studies have suggested that both hepatocytes and biliary cells (cholangiocytes) may give rise to iCCA. Consistent with the plasticity of these cell lineages, primary liver carcinomas exhibit a phenotypic range from hepatocellular carcinoma (HCC) to iCCA, with intermediates along this spectrum. Here, we generated mouse models to examine the consequence of targeting mutant Kras and Tp53, common alterations in human iCCA, to different adult liver cell types. Selective induction of these mutations in the SOX9+ population, predominantly consisting of mature cholangiocytes, resulted in iCCA emerging from premalignant biliary intraepithelial neoplasia (BilIN). In contrast, adult hepatocytes were relatively refractory to these mutations and formed rare HCC. In this context, injury accelerated hepatocyte-derived tumorigenesis and promoted a phenotypic switch to iCCA. BilIN precursor lesions were absent in the hepatocyte-derived iCCA models, pointing toward distinct and direct emergence of a malignant cholangiocytic phenotype from injured, oncogenically primed hepatocytes. Tp53 loss enhanced the reprogramming of hepatocytes to cholangiocytes, which may represent a mechanism facilitating formation of hepatocyte-derived iCCA. Overall, our work shows iCCA driven by Kras and Tp53 may originate from both mature cholangiocytes and hepatocytes, and factors such as chronic liver injury and underlying genetic mutations determine the path of progression and resulting cancer phenotype.Significance: The histopathogenesis of biliary tract cancer, driven by Tp53 and Kras mutations, can be differentially impacted by the cell of origin within the mature liver as well by major epidemiologic risk factors. Cancer Res; 78(16); 4445-51. ©2018 AACR.

Thinking beyond peritoneal carcinomatosis: imaging spectrum of unusual disseminated peritoneal entities.

Although peritoneal carcinomatosis is the most common entity involving the peritoneum diffusely, a vast array of unusual diseases may affect the peritoneal surfaces. These entities can be further categorized into infectious, neoplastic, and miscellaneous, and miscellaneous conditions. Cross-sectional imaging, including computed tomography and magnetic resonance imaging are excellent modalities for further characterization of these unusual diseases. For some of the conditions, imaging-specific is achievable. For others, the diagnosis can be favored when clinical and/or cross-sectional features coexist.