Maura O’Neil

Impact of stem cell marker expression on recurrence of TACE-treated hepatocellular carcinoma post liver transplantation

AbstractBackgroundLiver transplantation is the most effective therapy for cirrhosis-associated hepatocellular carcinoma (HCC) but its utility is limited by post-transplant tumor recurrence. Use of the Milan, size-based criteria, has reduced recurrence rate to less than 10% but many patients remain ineligible. Reduction of tumor size with local therapies has been used to “downstage” patients to allow them to qualify for transplantation, but the optimal criteria to predict tumor recurrence in these latter patients has not been established. The existence of a progenitor cell population, sometimes called cancer stem cells (CSCs), has been proposed to be one mechanism accounting for the chemotherapy resistance and recurrence of hepatocellular carcinoma. The aim of this study was to determine if transcatheter arterial chemoemolization (TACE) treated tumors have increased CSC marker expression and whether these markers could be used to predict tumor recurrence.MethodsFormalin fixed specimens were obtained from 39 HCC liver explants (23 with no treatment and 16 after TACE). Immunohistochemical staining was performed for EpCAM, CD44, CD90, and CD133. Staining for each marker was scored 0–3 by evaluating the number and intensity of positive tumor cells in 5 hpf of tumor in each specimen.ResultsTACE treated tumors displayed greater necrosis and fibrosis than non-TACE treated samples but there were no differences in morphology between the viable tumor cells of both groups. In TACE treated specimens, the staining of both EpCAM and CD133 was greater than in non-TACE specimens but CD44 and CD90 were the same. In the TACE group, the presence of high EpCAM staining was associated with tumor recurrence. Four of ten EpCAM high patients recurred while 0 of 6 EpCAM low patients recurred (P = 0.040). None of the other markers predicted recurrence.ConclusionHigh pre-transplant EpCAM staining predicted HCC recurrence. This suggests that the abundance of tumor cells with a CSC phenotype may be a critical factor in the likelihood of tumor recurrence in patients receiving liver transplantation after TACE.

Hepatitis C and alcohol exacerbate liver injury by suppression of FOXO3.

Hepatitis C virus (HCV) infection exacerbates alcoholic liver injury by mechanisms that include enhanced oxidative stress. The forkhead box transcription factor FOXO3 is an important component of the antioxidant stress response that can be altered by HCV. To test whether FOXO3 is protective for alcoholic liver injury, we fed alcohol to FOXO3(-/-) mice. After 3 weeks, one third of these mice developed severe hepatic steatosis, neutrophilic infiltration, and >10-fold alanine aminotransferase (ALT) elevations. In cell culture, either alcohol or HCV infection alone increased FOXO3 transcriptional activity and expression of target genes, but the combination of HCV and alcohol together caused loss of nuclear FOXO3 and decreased its transcriptional activity. This was accompanied by increased phosphorylation of FOXO3. Mice expressing HCV structural proteins on a background of reduced expression of superoxide dismutase 2 (SOD2; Sod2(+/-)) also had increased liver sensitivity to alcohol, with elevated ALT, steatosis, and lobular inflammation. Elevated ALT was associated with an alcohol-induced decrease in SOD2 and redistribution of FOXO3 to the cytosol. These results demonstrate that FOXO3 functions as a protective factor preventing alcoholic liver injury. The combination of HCV and alcohol, but not either condition alone, inactivates FOXO3, causing a decrease in expression of its target genes and an increase in liver injury. Modulation of the FOXO3 pathway is a potential therapeutic approach for HCV-alcohol-induced liver injury.

Moderate (2%, v/v) Ethanol Feeding Alters Hepatic Wound Healing after Acute Carbon Tetrachloride Exposure in Mice

Wound healing consists of three overlapping phases: inflammation, proliferation, and matrix synthesis and remodeling. Prolonged alcohol abuse can cause liver fibrosis due to deregulated matrix remodeling. Previous studies demonstrated that moderate ethanol feeding enhances liver fibrogenic markers and frank fibrosis independent of differences in CCl4-induced liver injury. Our objective was to determine whether or not other phases of the hepatic wound healing response were affected by moderate ethanol after CCl4 exposure. Mice were fed moderate ethanol (2% v/v) for two days and then were exposed to CCl4 and euthanized 24–96 h later. Liver injury was not different between pair- and ethanol-fed mice; however, removal of necrotic tissue was delayed after CCl4-induced liver injury in ethanol-fed mice. Inflammation, measured by TNFα mRNA and protein and hepatic Ly6c transcript accumulation, was reduced and associated with enhanced hepatocyte apoptosis after ethanol feeding. Hepatocytes entered the cell cycle equivalently in pair- and ethanol-fed mice after CCl4 exposure, but hepatocyte proliferation was prolonged in livers from ethanol-fed mice. CCl4-induced hepatic stellate cell activation was increased and matrix remodeling was prolonged in ethanol-fed mice compared to controls. Taken together, moderate ethanol affected each phase of the wound healing response to CCl4. These data highlight previously unknown effects of moderate ethanol exposure on hepatic wound healing after acute hepatotoxicant exposure.

CASTLE Thyroid Tumor: A Case Report and Literature Review

Carcinoma showing thymus-like differentiation is a rare tumor of the thyroid gland, which is structurally similar to thymic tissue. Overall, it has a favorable prognosis. Radiotherapy has been shown to be an effective local treatment, but there have been reports of distant recurrence. It has been suggested that adding chemotherapy may decrease the risk of recurrence. Here, we present a case report of a patient with a large tumor and extrathyroidal extension. The patient was treated with surgery, radiotherapy, and cisplatin with acceptable toxicity. The patient is free of locally recurrent or distant disease at 3 years.

Tumors and Tumor-Like Conditions

Liver tumors are classified as benign or malignant and malignant tumors can be primary or metastatic. Primary liver tumors may originate from hepatocytes, bile duct epithelium or endothelial cells. The most common tumors of liver are hemangiomas and the most common malignant tumors of the liver are hepatocellular carcinomas. Metastases are much more common than primary malignant tumors.

Liver Transplantation Pathology

Liver transplantion is the treatment for end stage chronic liver diasese, acute liver failure with massive liver necrosis, malignant liver tumors, and chronic metabolic or genetic diseases. The interpretation of liver biopsies to evaluate the donor liver as well as the changes that occur after transplant requires specialized knowledge related to liver transplantation such as the following: graft preservation/reperfusion injury, vascular and biliary tract injuries, cell mediated and antibody mediated rejection, complications of immunosuppression, and recurrence of original liver disease.

Patterns of Liver Injury

Liver response to injury includes a relatively narrow spectrum of morphologic changes, and accordingly there are only several pathologic patterns that can be recognized microscopically. First of all one must determine if the liver biopsy is from a native liver or from a liver transplant. If it is native liver one must decide if the liver was biopsied for a mass lesion requiring a tumor diagnosis or a diffuse liver disease. Relevant patient data provided by the clinician is always welcome and encouraged to provide appropriate contextual review. First, diffue liver disease should be divided into acute and chronic liver disease. Next, the liver is classified according the predominent pattern of injury. Then, after incorporation of clinical information and laboratory data, a differential diagnosis can be rendered.

Handling and Processing of Liver Biopsies

Handling and processing of the liver biopsy includes gross examination and identification, fixation, embedding in paraffin and sectioning, and routine and special staining of sections.

Indications and Techniques of Liver Biopsy

Generally speaking liver pathology may be studied in many pathologic samples, such as those obtained at autopsy, hepatectomy, partial liver resection, surgical and medical biopsy. The latter two modalities are of greatest significance for the clinicians and accordingly in this book we will mostly discuss the pathology of the liver as seen in liver biopsies.

Common Medical Liver Diseases

Common medical disease affecting the liver include acute and chronic viral hepatitis, drug-induced liver injury, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, biliary obstruction, alcohol induced liver disease, non-alcohol fatty liver disease, hereditary hemochromatosis, Wilson disease, and α1-antitrypsin deficiency.