Faculty Bibliography

Cirrhosis is a progressive, diffuse process of liver fibrosis that is characterized by architectural distortion and the development of a spectrum of nodules ranging from benign regenerative nodules to premalignant dysplastic nodules to overtly malignant hepatocellular carcinoma. The purpose of this essay is to demonstrate the ex vivo MR and pathology findings of these nodules as well as other masses that can be seen in the cirrhotic liver. The optimal conditions under which ex vivo imaging can be performed allow greater spatial resolution than that achieved with in vivo imaging, without artifacts that may degrade image quality. Clearly, contrast-enhanced MRI is essential for both the diagnosis and the characterization of focal lesions in the cirrhotic liver. However, the use of ex vivo imaging precludes the evaluation of these important in vivo pulse sequences

Following a report of skeletal muscle regeneration from bone marrow cells, we investigated whether hepatocytes could also derive in vivo from bone marrow cells. A cohort of lethally irradiated B6D2F1 female mice received whole bone marrow transplants from age-matched male donors and were sacrificed at days 1, 3, 5, and 7 and months 2, 4, and 6 posttransplantation (n = 3 for each time point). Additionally, 2 archival female mice of the same strain who had previously been recipients of 200 male fluorescence-activated cell sorter (FACS)-sorted CD34(+)lin(-) cells were sacrificed 8 months posttransplantation under the same protocol. Fluorescence in situ hybridization (FISH) for the Y-chromosome was performed on liver tissue. Y-positive hepatocytes, up to 2.2% of total hepatocytes, were identified in 1 animal at 7 days posttransplantation and in all animals sacrificed 2 months or longer posttransplantation. Simultaneous FISH for the Y-chromosome and albumin messenger RNA (mRNA) confirmed male-derived cells were mature hepatocytes. These animals had received lethal doses of irradiation at the time of bone marrow transplantation, but this induced no overt, histologically demonstrable, acute hepatic injury, including inflammation, necrosis, oval cell proliferation, or scarring. We conclude that hepatocytes can derive from bone marrow cells after irradiation in the absence of severe acute injury. Also, the small subpopulation of CD34(+)lin(-) bone marrow cells is capable of such hepatic engraftment

Small, extraportal, hepatic parenchymal cells, positive for biliary-type cytokeratins, may represent hepatic stem cells, canals of Hering (CoH), and/or ductal plate remnants. We evaluated these cells 3 dimensionally in normal human liver and massive necrosis. Tissues from normal human livers and from 1 liver with acetaminophen-induced massive necrosis were serially sectioned, immunostained for cytokeratin 19 (CK19), and sequentially photographed. Images were examined to determine 3-dimensional relationships among CK19-positive cells. Immunostains for other hepatocyte and progenitor cell markers were examined. In normal livers, intraparenchymal CK19-positive cells lined up as linear arrays in sequential levels. One hundred of 106 (94.3%) defined, complete arrays within levels examined, most having 1 terminus at a bile duct, the other in the lobule, beyond the limiting plate. In massive necrosis, there were 767 individual CK19-positive cells or clusters around a single portal tract, 747 (97.4%) of which were spatially related forming arborizing networks connected to the interlobular bile duct by single tributaries. C-kit was positive in normal CoH. CK19 co-expressed with HepPar1, c-kit, and alpha-fetoprotein (AFP) in parenchymal cells in massive necrosis. Small, extraportal, biliary-type parenchymal cells represent cross-sections of the CoH that radiate from the portal tract, usually extending past the limiting plate into the proximate third of the hepatic lobule. The 3-dimensional structure of ductular reactions in massive necrosis suggests that these reactions are proliferations of the cells lining the CoH. Therefore, the CoH consist of, or harbor, facultative hepatic stem cells in humans

The great advances in radiologic imaging of the last two decades have focused attention on hepatic nodular lesions. Various entities with a nodular appearance are predominantly composed of hepatocytes or tumor cells of hepatocytic origin, including benign and malignant neoplasms as well as tumorlike lesions. Differential diagnosis of these nodules can often be difficult, especially in the limited material of a needle biopsy specimen. The histological features that can be of help in this regard are the focus of this review. In noncirrhotic livers, differential diagnoses include liver cell adenoma, focal nodular hyperplasia, large regenerative nodule, nodular regenerative hyperplasia, partial nodular transformation, compensatory hyperplasia, focal fatty change, and well-differentiated hepatocellular carcinoma. Poorly differentiated hepatocellular carcinoma must be distinguished from other malignant tumors, especially metastatic, poorly differentiated adenocarcinoma. In cirrhotic livers, the differential diagnoses include large regenerative nodule, focal fatty change, low-grade dysplastic nodule, high-grade dysplastic nodule, and hepatocellular carcinoma