Faculty Bibliography

The canals of Hering (CoH), converging from the hepatic lobule onto the portal tract, connect bile canaliculi to the interlobular bile ducts, and represent the most proximal portion of the bile drainage pathway with a cholangiocyte lining. In this study we sought to ascertain whether this proximal pathway is involved by the disease process in primary biliary cirrhosis (PBC), which uniformly affects small bile ducts while sparing medium- and large-sized ducts. Ten biopsy specimens with early-stage PBC were compared with 6 normal control livers. Adjacent 4-micron-thick sections of routinely processed, formalin-fixed tissue were immunostained for CK19 and HLA-DR. Each terminal portal tract was assigned a stage: 0, normal; 1, bile duct damage or loss; 2, bile ductular proliferation; or 3, periportal fibrosis. The ratio of the number of CoH to number of portal tracts (i.e., the c/p ratio) was calculated for the control biopsies and individual portal tracts at each stage of PBC. The numbers of CoH were decreased in all stages of PBC (P <0.0001), with the fewest found around portal tracts at stages 0 and 1 and the most around portal tracts at stages 2 and 3, but never at normal levels. HLA-DR was expressed focally on bile ducts and CoH in PBC, but was absent in normal controls. We conclude that CoH are destroyed in PBC in concert with the destruction of small bile ducts. This destruction appears to be an early event, because CoH numbers are lowest around stage 0 portal tracts, which still contain normal bile ducts

BACKGROUND/AIM: Proliferative bile ductular reactions occur in a variety of liver diseases in humans. It is a matter of debate whether such reactions result from progenitor cell proliferation with biliary and hepatocytic differentiation, versus biliary metaplasia of damaged hepatocytes. We investigated bile ductular reactions in liver diseases, paying particular attention to the presence of cells with intermediate (hepatocytic/biliary) features (oval-like cells). METHODS: Five specimens each were selected of submassive hepatic necrosis and cirrhosis due to hepatitis B, hepatitis C, autoimmune hepatitis, alcohol injury, primary biliary cirrhosis and primary sclerosing cholangitis. Immunohistochemical stains were performed for biliary markers (cytokeratins [CKs] 7 and 19), as well as hepatocytic markers (HepParl and alpha-fetoprotein[AFP]) in sequential sections. The degree of staining of each cell type (biliary, hepatocytic, intermediate) was graded semiquantitatively. RESULTS: Hepatocytes always stained diffusely for HepParl, occasionally for CK7, and rarely for CK19. Biliary cells were always diffusely positive for CK7 and CK19, and rarely for HepParl. Intermediate cells were identified in all cases and showed widespread staining for both HepParl and CK7, and less commonly for CK19. AFP was not expressed in any cell type. The morphologic and immunohistochemical features of bile ductular reactions were similar in the different diseases. CONCLUSIONS: Proliferating hepatic parenchymal cells with intermediate (hepatocytic/biliary) morphologic features and combined immunophenotype can be identified in a variety of acute and chronic liver diseases. The similarity of bile ductular reactions among chronic hepatitic, alcoholic and biliary diseases suggests that they result from proliferation of oval-like progenitor cells

OBJECTIVE: The objective of this study was to determine the sensitivity and specificity of sonography as an aid in detecting hepatocellular carcinomas and dysplastic nodules using explantation correlation in patients with cirrhosis and no known hepatocellular carcinomas. MATERIALS AND METHODS: The sonography reports of 200 patients with cirrhosis who underwent sonography and then underwent liver transplantation within 90 days were retrospectively reviewed for focal solid liver lesions. All focal solid masses detected on sonography were considered possible hepatocellular carcinomas. The sonographic findings were compared with thin-section explanted liver pathologic results. RESULTS: Twenty-seven patients (13.5%) had hepatocellular carcinoma at explantation, including four patients with diffuse, multifocal tumors. Eight of the 39 lesions were detected on sonography for a patient sensitivity of 29.6% and a lesion sensitivity of 20.5%. Sonography revealed three (75%) of four hepatocellular carcinomas larger than 5 cm in diameter, one (50%) of two hepatocellular carcinomas with diameters of 3.1-5.0 cm, one (20%) of five hepatocellular carcinomas with diameters of 2.1-3.0 cm, three (13.6%) of 22 hepatocellular carcinomas with diameters of 1-2 cm, and no lesions with diameters smaller than 1 cm. Forty-two patients (21%) had a total of 126 dysplastic nodules including two patients with innumerable lesions. Sonography depicted only two dysplastic nodules, for a patient sensitivity of 4.8% and a lesion sensitivity of 1.6%. The overall specificity of sonography for either hepatocellular carcinomas or dysplastic nodules was 96%. CONCLUSION: Sonography has low sensitivity but high specificity in revealing hepatocellular carcinomas and dysplastic nodules in patients with a cirrhotic liver requiring liver transplantation. In these patients, sonography should not be the sole imaging modality used for lesion detection before transplantation

In the last decade, careful examination of explanted cirrhotic livers in liver transplant centers around the world has confirmed the findings of the earlier Japanese investigators: DNs (by this or any other name) represent hepatic, premalignant lesions in chronic liver disease. Careful examination of their gross and microscopic morphologies has led to the hypothesis of precirrhotic, spreading clonal expansions that are resistent to scarring, and that result in neoplastic islands of hepatic parenchyma. The resultant distinctive nodules, often marked by features suggestive of their clonality (such as increased pigment), are at increased risk for subsequent carcinomatous events, thereby giving rise to HCC. Specialized molecular and immunohistochemical studies confirm many aspects of this hypothesis. In suggesting that some aspects of DN pathophysiology are not integral to the carcinogenetic pathway (i.e., inhibition of HSC inactivation), this hypothesis serves a broader purpose, explaining the various settings in which early HCCs are found in cirrhotic explants and in wedge resections of radiographically defined lesions. Discrepancies between Japanese and non-Japanese investigations regarding dysplasia and early HCCs reflect not different biologic pathways but differences in detection, interpretation, and application of nomenclature. These differences may fade away as more international collaborative work brings investigators of diverse nationalities into regular contact, supporting movement toward a commonly acceptable nomenclature and set of diagnostic criteria. Ultimately, an understanding of the pathophysiology of these lesions, through more detailed molecular and physiologic studies, should lead to more efficient and available early detection, and perhaps chemoprevention approaches to hepatic malignancy

The standard paradigm of embryologic development and adult tissue reconstitution posits unidirectional, hierarchical lineages. The presumed mechanisms underlying these differentiative pathways are gene restrictions, such as methylation and heterochromatin formation, which are commonly described as irreversible. However, recent discoveries regarding multi-organ stem cells demonstrate that 'true plasticity' exists, with cells of one organ turning into cells of other organs, including differentiative transformations that cross barriers between tissues derived from different primitive germ layers. These findings, along with earlier experiments into heterokaryon formation and longstanding recognition of reactive and neoplastic lesions in humans and animals, suggest that lineage pathways are not, in fact, unidirectional. Moreover, physiologic mechanisms of reversal of gene restrictions have been recognized. Therefore, in response to these observations, we suggest a new paradigm of cell plasticity, elucidating three guiding principles of 'genomic completeness', 'uncertainty of cell characterization', and 'stochastic nature of cell origins and fates'. These principles imply a change in the way data can be interpreted and could alter subsequent hypothesis formation. This new paradigm will hopefully lead us forward to a more flexible and creative exploration of the potential of adult vertebrate cells

RATIONALE AND OBJECTIVES: The authors performed this study to determine whether, on the basis of the vascular profile, low-grade siderotic dysplastic nodules are premalignant lesions. MATERIALS AND METHODS: The authors used a monoclonal antibody specific for smooth muscle actin to stain 18 siderotic low-grade dysplastic nodules (mean size, 0.7 cm) from nine patients. Two pathologists counted the number of unpaired arteries per high-power field in siderotic dysplastic nodules and background siderotic regenerative nodules by using two techniques (conventional and hot spot). RESULTS: The number of unpaired arteries seen with the conventional counting technique in low-grade siderotic dysplastic nodules (range, 1-14; mean, 3.8) was significantly greater (P = .004) than that seen in background siderotic regenerative nodules (range, 0-3; mean, 1.2). Similarly, the number of unpaired arteries seen with the hot spot technique in low-grade siderotic dysplastic nodules (range, 0-14; mean, 5.2) was significantly greater (P = .005) than that seen in background siderotic regenerative nodules (range, 0-6; mean, 1.9). CONCLUSION: On the basis of the vascular profile, low-grade siderotic dysplastic nodules should be considered premalignant lesions. Further research is needed to help differentiate these lesions from siderotic regenerative nodules with magnetic resonance imaging

BACKGROUND. Dysplastic nodules (DNs) recently have been identified as preneoplastic lesions of hepatocellular carcinoma (HCC). To test an alternative hypothesis regarding DN development, in which we have suggested that DNs develop as an infiltrating clonal expansion in advance of, or parallel to cirrhosis, the authors investigated the rates of apoptosis and proliferation in human hepatocarcinogenesis. METHODS. The authors performed terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay and proliferation cell nuclear antigen (PCNA) staining in 11 low-grade DNs, 8 high-grade DNs including 3 cases with HCC subnodules, 10 small HCCs, and 29 cases of surrounding cirrhotic nodules. Hepatocellular carcinoma subnodules were present in three cases of high DNs. They determined TUNEL-labeling indices (LIs) and PCNA-LIs as the percentage of positive hepatocyte nuclei per 500 randomly counted cells. RESULTS. TUNEL-LIs (mean standard deviation) were 0.8 +/- 0.82 in cirrhotic nodules, 1.0 +/- 0.98 in low-grade DNs, 3.0 +/- 4.33 in high-grade DNs, 8.7 +/- 7.71 in HCC subnodules of high-grade DNs, and 3.2 +/- 3.58 in small HCCs. The peak values of apoptotic activity were higher in high-grade DNs and HCCs than in low-grade DNs and cirrhotic nodules. Each case of low-grade DN showed a low to medium level of apoptotic activity when compared with those of the four surrounding cirrhotic nodules. The PCNA-LIs were 2.6 +/- 1.35 in cirrhotic nodules, 4.5 +/- 2.31 in low-grade DNs, 15.3 +/- 10.50 in high-grade DNs, 25.4 +/- 5.25 in HCC subnodules of high-grade DNs, and 34.9 +/- 15.70 in small HCCs. The peak values gradually increased, although only HCC showed significantly elevated proliferation activity. The differences of PCNA-LIs and TUNEL-LIs, measured in each case, were 1.7 +/- 1.89 in cirrhotic nodules, 3.6 +/- 2.43 in low-grade DNs, 7.9 +/- 5.69 in high-grade DNs, 16.2 +/- 2.87 in HCC subnodules of high-grade DNs, 28.2 +/- 13.97 in small HCCs. At all stages of hepatocarcinogenesis, the rates of cell proliferation were higher than apoptosis, allowing a preferential net gain of (pre)neoplastic cells, and it was significantly increased in small HCCs. In regenerative cirrhotic nodules, 14% (4 cases) showed higher rates of apoptosis than proliferation. CONCLUSIONS. The regulation/clysregulation of apoptosis of (pre)neoplastic cells as well as of proliferation may play an important role in the process of hepatocarcinogenesis. Cancer 2001;92:2733-8. (C) 2001 American Cancer Society

Purification of rare hematopoietic stem cell(s) (HSC) to homogeneity is required to study their self-renewal, differentiation, phenotype, and homing. Long-term repopulation (LTR) of irradiated hosts and serial transplantation to secondary hosts represent the gold standard for demonstrating self-renewal and differentiation, the defining properties of HSC. We show that rare cells that home to bone marrow can LTR primary and secondary recipients. During the homing, CD34 and SCA-1 expression increases uniquely on cells that home to marrow. These adult bone marrow cells have tremendous differentiative capacity as they can also differentiate into epithelial cells of the liver, lung, GI tract, and skin. This finding may contribute to clinical treatment of genetic disease or tissue repair

PURPOSE: To determine the sensitivity and specificity of magnetic resonance (MR) imaging for detection of hepatocellular carcinoma (HCC) and dysplastic nodules (DNs) by using explantation correlation in patients with cirrhosis and no known HCC. MATERIALS AND METHODS: Seventy-one patients without a known history of HCC who underwent MR imaging and subsequent transplantation within 90 days were examined. Breath-hold turbo short inversion time inversion-recovery and/or T2-weighted turbo spin-echo MR images were obtained. Dynamic two- or three-dimensional gadolinium-enhanced gradient-echo MR images were obtained in the hepatic arterial, portal venous, and equilibrium phases. Prospective MR image interpretations were compared directly with explanted liver pathologic results. RESULTS: Eleven (15%) of 71 patients had hepatic malignancies; MR imaging enabled diagnosis of tumor in six (54%) of 11 patients. On a lesion-by-lesion basis, MR imaging depicted 11 of 20 hepatic neoplasms, for an overall sensitivity of 55%. MR imaging depicted four (80%) of five lesions larger than 2 cm, six (50%) of 12 lesions 1-2 cm, and one (33%) of three lesions smaller than 1 cm. MR imaging depicted only nine (15%) of 59 DNS: The specificities of MR imaging for detection of HCC and DNs on a per patient basis were 60 (86%) of 70 patients and 53 (85%) of 62 patients, respectively. CONCLUSION: MR imaging is insensitive for the diagnosis of small (<2-cm) HCCs and DNS: