Primary hepatic carcinoid tumor presenting as Cushing's syndrome.

Hepatic carcinoid tumors are very uncommon; most are clinically non-functional and very few present with the symptoms of carcinoid syndrome. ACTH-producing carcinoid tumors most commonly originate in the lung or thymus and present insidiously with bronchospasm and/or chest mass. Occasionally, ectopic ACTH syndromes have been reported in association with pancreatic islet cell tumors, medullary thyroid cancer, pheochromocytoma, small-cell lung carcinoma, and rarely, ovarian and prostate tumors. We report here a patient with an ectopic ACTH-secreting primary hepatic carcinoid tumor who presented with cushingoid appearance, profound proximal muscle weakness, severe lower extremity edema, and markedly elevated urinary free cortisol. ACTH levels were in the low normal range. A solitary vascular hepatic lesion was found on magnetic resonance imaging, which was isodense with the surrounding liver on octreotide scan and photopenic on an 18-fluorodeoxyglucose (18FDG)-positron emission tomography (PET) scan. Following surgical resection of the hepatic tumor, histopathology confirmed an ACTH-secreting neuroendocrine tumor (NET), the patient had complete resolution of hypercortisolemic symptoms and remains in remission, now 4 yr after hepatic tumor resection. This case reports the first ACTH-secreting primary hepatic NET presenting as ectopic Cushing's syndrome. Interesting aspects of this case include the presence of a pituitary incidentaloma, the low normal ACTH, and photopenia on 18FDG-PET imaging.

Transmission of hepatitis B infection from hepatitis B core antibody--positive liver allografts is prevented by lamivudine therapy.

Donor shortage has led to the use of hepatitis B core antibody (anti-HBc)--positive (anti-HBc(+)) liver allografts for patients in need of relatively urgent orthotopic liver transplantation (OLT). Because anti-HBc(+) allografts transmit hepatitis B virus (HBV) infection at a high rate, effective prophylaxis is required. We assessed the effectiveness of lamivudine in preventing HBV transmission by anti-HBc(+) allografts. Between March 1996 and March 2000 at Cedars-Sinai Medical Center (Los Angeles, CA), 15 of 169 patients (8.9%) received liver allografts from anti-HBc(+) donors. Six patients were hepatitis B surface antigen (HBsAg)(+) (group 1), and 9 patients were HBsAg negative (HBsAg(-); group 2) before OLT. All patients were administered lamivudine, 100 or 150 mg/d, orally after OLT. Patients who were HBsAg(+) before OLT also were administered hepatitis B immunoglobulin (HBIG) prophylaxis. Hepatitis B serological tests were performed on all patients, and HBV DNA was determined in liver tissues in 10 patients. All 15 patients remained HBsAg(-) at their last follow-up 2 to 40 months (mean, 17 months) post-OLT. All patients in group 1 had antibody to HBsAg (anti-HBs) titers greater than 250 mIU/mL post-OLT (mean follow-up, 20 months; range, 7 to 40 months). Of the 2 patients in group 1 who underwent liver biopsy after OLT, 1 patient had detectable hepatic HBV DNA despite being anti-HBs(+) and HBsAg(-). Among the patients in group 2, none acquired anti-HBc or HBsAg. Hepatic HBV DNA was undetectable in the 7 patients in group 2 who underwent liver biopsy after OLT. Anti-HBc(+) allografts can be safely used in patients who undergo OLT for chronic hepatitis B and susceptible transplant recipients if prophylaxis with combination HBIG and lamivudine or lamividine alone is administered after OLT, respectively. However, more data are needed to determine the efficacy of lamivudine monotherapy in preventing transmission of HBV infection from anti-HBc(+) liver allografts to susceptible recipients.

Primary liposarcoma of the liver: a case report and review of literature.

Liposarcoma is a rare mesenchymal malignant tumor, which usually originates in the retroperitoneum and the extremities. Seven cases of primary liposarcoma of the liver have been previously reported. We present the eighth case, which occurred in an adult female patient. Primary liposarcoma of the liver, although extremely rare, must be considered in the differential diagnosis of a hepatic mass that develops in a noncirrhotic liver, especially in patients who are potential candidates for orthotopic liver transplantation. Liposarcoma is an absolute contraindication for liver transplantation.

Immortalized intrahepatic mouse biliary epithelial cells: immunologic characterization and immunogenicity.

Nonsuppurative destructive cholangitis (NSDC), a process of T-cell-mediated destruction of biliary epithelia observed in primary biliary cirrhosis (PBC), graft-versus-host disease (GVHD), and hepatic allograft rejection (HAR), also occurs in the B10. D2-->BALB/c model of GVHD. To advance studies of immunopathogenesis in this murine model, we immortalized 4 BALB/c intrahepatic biliary epithelial cell (BEC) lines as a reliable source of target cells. Freshly isolated BEC, as well as each cell line, expressed cytokeratin-19 (CK-19), epithelial cell adhesion molecule (EPCAM) and cystic fibrosis transmembrane conductance regulator (CFTR). None expressed albumin. Immortalized cells also expressed SV40 large T antigen. Class I major histocompatibility complex (MHC) was expressed by >97% of immortalized cells, while class II MHC and intercellular adhesion molecule-1 (ICAM-1) expression ranged from 0% to 13% and 14% to 74%, respectively. Interferon gamma (IFN-gamma) induced aberrant class II MHC expression and increased expression of ICAM-1. Variable proportions of immortalized cells expressed B7-1/B7-2 molecules and FAS. IFN-gamma significantly reduced B7-1 expression in some lines and significantly increased B7-2 expression in others. Allografts of freshly isolated and immortalized BEC injected into subscapular fat pads spontaneously formed duct-like structures. Inflammation was absent in BALB/c recipients. In contrast, inflammatory lesions in B10.D2 recipients were reminiscent of NSDC. Our results indicate that BALB/c-immortalized intrahepatic biliary cells: 1) retain the phenotype of mouse BEC; 2) can be induced to express aberrant class II MHC and increased ICAM-1; 3) express costimulatory B7-1/B7-2 molecules and FAS; and 4) spontaneously form duct-like structures after in vivo injection that are immunogenic in B10.D2 mice. These cell lines should facilitate future studies of the immunopathogenesis of NSDC in the B10. D2-->BALB/c murine model.

Estimation of tumor stage and lymph node status in patients with colorectal adenocarcinoma using probabilistic neural networks and logistic regression.

Staging colorectal adenocarcinoma on the basis of biopsy specimens could identify patients who might benefit from neoadjuvant therapy without undergoing resection first. In this study, we evaluated the ability of artificial neural networks with genetic algorithms and multivariate logistic regression to predict the stage of 99 patients with primary colorectal adenocarcinoma by analyzing age, tumor grade, and immunoreactivity to p53 and bcl-2 with use of endoscopically obtained biopsy specimens. We correlated results with regional lymph node status and tumor stage, identified in subsequent colectomy specimens. bcl-2 and p53 protein expression were demonstrated by immunohistochemical methods, using formalin-fixed, paraffin-embedded biopsy tissues. Tumor grade was evaluated in hematoxylinand eosin-stained sections. Patients were divided into training (n = 75) and testing cases (n = 24). Several probabilistic neural networks with genetic algorithm models were trained, using the four prognostic features as input neurons and regional lymph node status or stage as output neurons. Data were analyzed with univariate statistics and multivariate logistic regression. The cases were divided into training (n = 40) and testing (n = 59). The best two models classified correctly the lymph node status of 20 of 24 test patients (specificity, 80%; sensitivity, 85%; positive predictive value, 86%) and the tumor stage of 21 of 24 test patients (specificity, 82%; sensitivity, 92%; positive predictive value, 85%), respectively. Tumor grade and p53 protein were statistically significant (P < .05) by analysis of variance for lymph node status and tumor stage. Logistic regression models with these two independent variables correctly estimated the probability of lymph node metastases in 44 of 59 test cases and the tumor stage of 43 of 59 test cases, respectively. Results indicated the usefulness of probabilistic neural networks in the population studied, but the findings should be validated with large groups of patients.

Hepatocellular carcinoma with fibrolamellar pattern in a patient with autoimmune cholangitis.

A 75-year-old woman with a 15-year history of autoimmune cholangitis underwent orthotopic liver transplantation because of progressive liver decompensation. A clinically unsuspected hepatocellular carcinoma was found. A portion of the tumor showed fibrolamellar differentiation. Hepatocellular carcinoma, either with the usual pattern or with a fibrolamellar pattern, is rare in the setting of primary biliary cirrhosis, but has been seen in the setting of autoimmune hepatitis. Autoimmune cholangitis is a relatively recently recognized form of autoimmune liver disease whose association with hepatocellular carcinoma has yet to be determined.

Novel human malignancy-associated gene (MAG) expressed in various tumors and in some tumor preexisting conditions.

We have identified a novel human malignancy-associated gene (MAG) expressed in various malignant tumors including glioblastomas and hepatocellular carcinomas (HCCs) and in tumor preexisting conditions such as hepatitis C virus- and hepatitis B virus-induced liver cirrhosis. The expression of MAG was characterized using reverse transcription-PCR (RT-PCR), rapid amplification of cDNA ends PCR, RNA dot blotting, RNase protection assay, and Northern blot analysis. Rapid amplification of cDNA ends PCR yielded a 536-bp MAG fragment in HCC, macroregenerative liver nodules with dysplasia, and liver cirrhosis but not in normal liver or placenta. By RT-PCR, MAG expression was not found in 12 different normal tissues but found in 46 of 51 (90%) premalignant and malignant tissues of various sites. Embryonic liver and brain were positive for MAG expression together with tumors from the same organs, but the corresponding normal adult tissues were negative. By RNase protection assay, MAG mRNA was expressed in the HepG2 liver tumor cell line and in an ovarian carcinoma but not in normal liver. The estimated transcript size from Northern blot analysis was 8.8 kb. This novel gene may play a role in the progression of premalignant conditions and in the development of HCC and other cancers.

Hepatocarcinogenesis (Z#2)/mutagenesis during initiation stage.

Previously, we developed a model for high incidence, endogenously generated hepatocellular carcinoma (HCC), the human alpha-1-antitrypsin (alpha1AT) Z gene transgenic mouse (Z#2). We now examine the potential utility of a model for endogenous carcinogenesis utilizing the Z#2 mouse also transgenic for the lacI gene, a convenient target for in vivo mutagenesis studies. We crossed the Z#2 line and mice transgenic for lambda/lacI shuttle vector (Big Blue), for determination of lacI mutant frequency during initiation of endogenous carcinogenesis. Five month old double transgenic mice (Z#2+/lacI+) successfully displayed: (1) the expected post-inflammatory stage of Z#2 carcinogenesis; and (2) hepatic lacI mutants measured at frequencies (10(-5)-10(-4)) useful to mutagenesis studies. In this study, hepatic lacI mutation frequencies in Z#2 transgenic mice appeared to be only slightly increased (< 2x) when compared to age matched negative controls. In the future, it may be important to reconcile possibly limited lacI mutagenesis at the time of initiation and demonstrated high incidence of hepatocarcinogenesis.

Rapid extension of left adrenocortical carcinoma into the right atrium.

Adrenocortical carcinoma is a rare tumor which can extend into the right heart via the inferior vena cava. We describe a case of a 26-year-old woman who had progressive shortness of breath, intermittent chest pain, and peripheral edema. A two-dimensional echocardiogram on hospital admission showed a large multinodular mass in the right atrium which extended into the inferior vena cava. Further studies showed that this mass was adrenocortical carcinoma. An echocardiogram performed 3 weeks before admission was completely normal. It appears that an adrenocortical carcinoma is capable of rapid growth up the inferior vena cava and into the right atrium.

Terbinafine hepatotoxicity: case report and review of the literature.

We report a patient who developed significant liver dysfunction following therapy with terbinafine. At the end of a 3 1/2-wk course of terbinafine, he developed progressive jaundice and pruritus. His serum bilirubin peaked at 30.9 mg/dl 3 wk after discontinuing terbinafine. A liver biopsy revealed mild to moderate mixed cellular infiltrate in the portal tracts, and hepatocellular and canicular cholestasis. His liver tests normalized 100 days after stopping terbinafine.

The application of image analysis and neural network technology to the study of large-cell liver-cell dysplasia and hepatocellular carcinoma.

Liver cell dysplasia (LCD) is considered a preneoplastic lesion, whose characterization and differentiation from hepatocellular carcinoma (HCC) and from the reactive changes seen in cirrhosis has been controversial. We studied 12 cases of LCD (large cell type) with image analysis techniques (IA) and compared the findings with those of HCC (n = 40), and a spectrum of non-neoplastic hepatic lesions including normal liver and cirrhosis (n = 49). A minimum of 200 Feulgen-stained nuclei were measured from each lesion with the CAS 200 image analysis system. The data were collected with the aid of CellSheet software. Thirty-four variables were measured, including geometric, textural, and photometric nuclear features and DNA ploidy. The data were analyzed with multivariate statistics and a backpropagation neural network (NN). Stepwise statistical analysis selected 22 variables that were statistically significant in the three groups with P values <.05. Various NN architectures were developed using these variables. The best NN architecture included a sigmoidal transfer function, 14 input, 16 hidden, and 3 output neurons. It trained to completion after 8,887 runs using 90% of the lesions. This NN yielded a 100% cross-validation rate for unknown cases. These data support the concept of LCD (large cell type) as a lesion that can be objectively distinguished from HCC and non-neoplastic liver. Our study also demonstrates the potential usefulness of IA for the evaluation of difficult histopathological problems.

Lack of hepatocyte growth factor receptor (c-met) gene expression in fulminant hepatic failure livers before transplantation.

To gain insight into liver regeneration mechanisms in fulminant hepatic failure, we compared gene expression of hepatocyte growth factor, its receptor c-met, c-myc, and albumin in human normal (4 cases) and fulminant (14 cases) livers by reverse transcription-polymerase chain reaction. In normal livers, hepatocyte growth factor gene was not expressed, whereas c-met, c-myc and albumin genes were always expressed. In fulminant hepatic failure, hepatocyte growth factor gene was expressed in 1 of 14 cases, c-met in none of 14 cases, c-myc in 10 of 14 cases, and albumin in 3 of 14 cases. By immunofluorescence, c-met protein was revealed in normal but not in fulminant hepatic failure liver tissue. Liver tissue is unlikely to account for high hepatocyte growth factor plasma levels typical for fulminant hepatic failure. Lack of its receptor (c-met) expression may explain a poor response of fulminant hepatic failure livers to exogenous hepatocyte growth factor that normally promotes liver growth and regeneration.

Comparison of histopathology in acute allograft rejection and recurrent hepatitis C infection after liver transplantation.

Recurrent hepatitis C infection after orthotopic liver transplantation (OLT) is frequent and may occur as early as a few weeks postoperatively. Early histopathological features of recurrent hepatitis C virus (HCV) infection may be modified by immunosuppressive therapy and can be difficult to differentiate from acute allograft rejection (AAR). Thus, we retrospectively compared histopathological features of liver biopsy specimens from two carefully selected patient groups: one with unequivocal recurrent hepatitis C, the other with unequivocal AAR. Index biopsy specimens obtained at the time of the appearance of liver test abnormalities after OLT and all serial liver biopsy specimens (2 to 13 per patient) were assessed under code and scored semiquantitatively for 44 histopathological variables. The index biopsy specimens from patients with recurrent HCV infection and AAR index biopsies (AAR-Ib) differed significantly (P < .05) for 11 features (10 features were statistically associated with AAR and 1 with early recurrence of HCV infection). Statistically significant features associated with AAR included bile duct injury with overlapping nuclei, lymphocytic infiltrates and necrosis, endothelialitis, portal inflammatory infiltrates containing eosinophils and polymorphonuclear leukocytes, hepatocyte mitoses, and zone 3 canalicular cholestasis. In contrast, the only statistically significant feature associated with early recurrent HCV was sinusoidal dilatation. Stepwise discriminant analysis showed that the presence of eosinophils in the portal inflammatory infiltrate, bile duct necrosis, and bile duct lymphocytic infiltrates were independently associated with AAR. However, serial biopsy specimens from patients with recurrent HCV infection showed statistically significant progression in scores for portal inflammation, portal lymphoid aggregates, and lobular inflammation. We conclude that (1) multiple histopathological features are associated with AAR; (2) early recurrent HCV infection is characterized by elevated alanine aminotransferase levels, positive HCV RNA by polymerase chain reaction (PCR), and absence of diagnostic histopathological features; and (3) serial biopsies are needed to demonstrate progression of histopathological features of recurrent hepatitis C.

Posttransplant lymphoproliferative disorder in liver allograft biopsies: a comparison of three methods for the demonstration of Epstein-Barr virus.

Posttransplant lymphoproliferative disorder (PTLD) is associated with Epstein-Barr virus (EBV), and may clinically resemble acute allograft rejection. Three methods to show EBV in tissue were evaluated in 15 liver allograft biopsies from 12 patients including four with PTLD: (1) semiquantitative polymerase chain reaction (PCR) for EBV DNA; (2) in situ hybridization for EBV RNA (EBER); and (3) immunoperoxidase for EBV latent membrane protein (LMP). Index cases had a PCR dot blot result of "positive" or "weak positive." Findings were correlated with histology, clinical data, therapy, and outcome. All four PTLD patients had a clinical diagnosis of acute rejection. All four showed EBV: PCR 4, EBER 4, LMP 3, Liver function tests were elevated in three, but EBV viral capsid antigen (VCA) IgM was not increased in three, but EBV viral capsid antigen (VCA) IgM was not increased in three. Immunosuppression was withdrawn and all four patients underwent a second transplantation. One died 4 days posttransplant with disseminated PTLD, two died of sepsis at 1.5 and 14 months, and one is well at 3 years without PTLD. Eleven biopsies without PTLD showed: acute rejection 7, acute rejection and hepatitis 1, hepatitis B 1, and non-inflammatory changes 2. In this group, EBV results included: PCR weak positive in 10 and 1+ in one, EBER negative in ten and rare positive cells in one, LMP negative in 11. Liver function tests were elevated in 10, whereas VCA IgM was not increased in three and increased in one. Patients with acute rejection were treated with increased immunosuppression: none developed PTLD, with follow-up of at least 6 months in nine cases. Two patients died within 4 months of biopsy. One patient with PTLD in tonsils had a liver biopsy showing both acute rejection and EBV (PCR 1+, rare EBER + small cells). Histological studies combined with special EBV detection methods, can be useful to evaluate atypical lymphoid infiltrates in liver allograft biopsies and confirmation of a diagnosis of PTLD. All three methods are useful; EBER and PCR are the most sensitive. EBER and LMP can use paraffin sections.

Hepatobiliary and pancreatic mucinous cystadenocarcinomas with mesenchymal stroma: analysis of estrogen receptors/progesterone receptors and expression of tumor-associated antigens.

Hepatobiliary and pancreatic mucinous cystadenocarcinomas with mesenchymal stroma are relatively rare neoplasms that occur preponderantly in women, suggesting a role for unidentified sex-specific factor(s) in the pathogenesis of these tumors. We used paraffin tissue immunohistochemical analysis with an appropriate panel of monoclonal antibodies to look for estrogen and progesterone receptors in two cases of hepatobiliary mucinous cystadenocarcinoma with mesenchymal stroma and one case of pancreatic mucinous cystadenocarcinoma. In all three of these cases, the nuclei of tumor stroma and, in the hepatic tumors, the nuclei of tumor epithelium, reacted with both antibodies. These data strongly suggest that a relationship to hormonal functions exists for these tumors. Because of the rarity of these tumors we also investigated the expression of a variety of oncoprotein antigens, epithelial antigens, and cytoskeletal antigens. The oncoprotein antigens, p53 and c-erbB-2, were focally expressed in hepatic and pancreatic tumor epithelium; bcl-2 was focally expressed in hepatic tumor epithelium. Keratin was strongly expressed in most epithelial cells. In addition, epithelial membrane antigen, carcinoembryonic antigen, and chromogranin were focally expressed in epithelial cells. Actin and vimentin were strongly expressed in most stromal cells but not in epithelial cells, and desmin expression was similar but less widespread.

Expression of HGF, its receptor c-met, c-myc, and albumin in cirrhotic and neoplastic human liver tissue.

Hepatocellular carcinoma (HCC) is a common type of cancer, with approximately 260,000 new cases each year, and liver cirrhosis is generally considered a major predisposing factor for HCC. However, specific changes of gene expression in liver cirrhosis and HCC remain obscure. The expression of genes for hepatocyte growth factor (HGF), its receptor c-met proto-oncogene, c-myc proto-oncogene, and albumin was analyzed. Gene expression was studied by PCR in seven normal human livers, nine cases of hepatitis C cirrhosis, 12 cases of alcoholic cirrhosis, two cases of liver adenoma, and 12 cases of HCC. HGF and c-met protein were revealed by immunofluorescent staining. HGF mRNA was not expressed in normal livers but was detected in adenomas, in 80% of HCC, and in some cirrhoses. Paraffin-embedded and fresh-frozen tissue samples yielded similar results. Immunohistochemical data correlated with PCR results regarding the overexpression of the HGF/c-met system in HCC. Albumin gene expression was decreased in HCC vs normal livers, consistent with altered function of tumor hepatocytes. The elevated expression of the HGF/c-met system in HCC may play a role in tumor development and/or progression. Tissue localization studies of HGF and its receptor c-met protein support the existence of both autocrine and paracrine mechanisms of action of HGF in HCC vs only a paracrine mechanism in normal liver.

Hepatic angiomyolipoma: two case reports of caudate-based lesions and review of the literature.

Two case reports of hepatic angiomyolipoma, both originating in the caudate lobe, are reported with a review of the literature. The liver is the second most common site of angiomyolipoma, an uncommon benign tumor of mixed mesenchymal origin. It is commonly diagnosed following abdominal pain or as an asymptomatic mass discovered on abdominal ultrasound or computed tomography scan. Of 74 cases reported, the lesions ranged from 0.3 to 36 cm in diameter and are noted between the first and eighth decade, with predominant female predilection. The right lobe is the most common site, with lesions arising in the caudate lobe comprising only five cases. The natural history of the hepatic lesion is unknown. Malignant invasion or metastatic disease has not been documented. Hepatic and renal angiomyolipoma can occur concurrently (13 of 60 cases), although the majority are not biopsy proven. Multicentric hepatic disease occurs. The correlation between tuberous sclerosis and hepatic angiomyolipoma is not confirmed histologically and occurs rarely. These lesions have a characteristic radiographic appearance due to high fat content. Histologically, angiomyolipoma are characterized by an admixture of adipose tissue, blood vessels, and smooth muscle cells. These lesions cannot reliably be differentiated from a malignant lesion based on clinical history, radiologic examination, and/or pathologic interpretation. If clinical suspicion for malignancy is low, then careful observation with serial radiologic follow-up is performed. The treatment for a symptomatic or suspicious lesion is resection, if feasible. Liver transplantation may be considered for large or centrally located lesions not amenable to resection.

Hepatitis C virus is not recoverable from liver tissue in cryptogenic cirrhosis: failure to identify hepatitis C virus-RNA using reverse transcription-mediated polymerase chain reaction.

Polymerase chain reaction (PCR) has been used to study liver biopsy tissue in patients with known or suspected hepatitis C virus (HCV). Recent studies of cryptogenic cirrhosis using PCR have been based on study of sera, and HCV has not been shown. The failure to show HCV in patients so studied has left unanswered the question of whether or not patients with cryptogenic cirrhosis could still harbor the virus in the liver. The authors studied liver tissue, obtained at the time of orthopic liver transplantation from 10 patients clinically diagnosed as having end-stage liver disease without demonstrable origin, so-called cryptogenic cirrhosis, using reverse transcription (RT)-PCR to try to recover HCV-RNA. Formalin-fixed, paraffin-embedded tissue was used. For comparison, the authors also studied similarly obtained samples from 10 patients with typical hepatitis C-associated cirrhosis and 10 patients with end-stage liver disease resulting from autoimmune hepatitis. The authors recovered HCV-RNA from 9 of 10 livers from patients with cirrhosis resulting from HCV, and 3 of 10 livers from patients with autoimmune hepatitis. HCV-RNA was not recovered from any of the livers of the 10 patients designated as having cryptogenic cirrhosis.