Steatohepatitic hepatocellular carcinoma: imaging findings with clinicopathological correlation.

AIM: To evaluate the clinicopathological and computed tomography (CT) and magnetic resonance imaging (MRI) findings of steatohepatitic hepatocellular carcinoma (SH-HCC). MATERIALS AND METHODS: Clinicopathological and radiological features were evaluated in 20 patients with SH-HCC. The diagnosis of SH-HCC was made histologically if the tumour had four of the following five characteristics: steatosis (>5% tumour cells), ballooning, Mallory-Denk bodies, interstitial fibrosis, and inflammation. All patients underwent dynamic CT and MRI. CT and MRI images were reviewed for morphological features including tumour size, presence, and distribution of fat, and patterns and degree of contrast enhancement. RESULTS: Obesity, hypertension, and history of heavy alcohol intake were common clinical findings observed in 10 (50%), 13 (65%), and 11 (55%) of the 20 patients, respectively. Steatosis and steatohepatitis were pronounced in the background liver in 12 (60%) and 10 (50%) patients, respectively. SH-HCC was moderately differentiated in 18 patients (90%) and well differentiated in two (10%). Pathologically, steatohepatitic features were diffuse in 12 (60%) of the 20 tumours and focal in eight (40%). Tumour size and the percentage of intratumoural steatosis were not correlated (r=0.17, p=0.47). On CT, 16 (80%) patients showed arterial phase enhancement and delayed washout. On MRI, 16 (80%) of 20 tumours showed prominent fatty deposition (10 diffusely, six focally) with arterial phase enhancement. CONCLUSIONS: SH-HCC is likely to show prominent fatty deposits with arterial phase enhancement on CT and MRI. A hypervascular lesion with prominent fatty change should raise the diagnostic suspicion of SH-HCC.

Overexpression of hepatocyte growth factor/scatter factor promotes vascularization and granulation tissue formation in vivo.

The effect of hepatocyte growth factor/scatter factor (HGF/SF) during wound healing in the skin was investigated, using HGF/SF-overexpressing transgenic mouse model. Histological analysis of HGF/SF transgenic mouse excisional wound sites revealed increased granulation tissue with marked vascularization. Northern blot analysis demonstrated that, relative to control, vascular endothelial growth factor (VEGF) expression in transgenic skin was significantly higher at baseline and was robustly up-regulated during wound healing. Elevated levels of VEGF protein were detected immunohistochemically, predominantly in endothelial cells and fibroblasts within the granulation tissue of HGF/SF transgenic skin. Serum levels of VEGF were also elevated in HGF/SF transgenic mice. Thus, results from our study suggest that HGF/SF has a significant effect on vascularization and granulation tissue formation during wound healing in vivo, involving with induction of VEGF.

Radioimmunometric assay for hepatitis B surface antigen on the surface of infected cells.

It has been difficult to differentiate hepatitis B surface antigen (HBsAg) on the cell surface from intracellular or intramembranous HBsAg that is not exposed to the host immune response. We describe here a radioimmunometric assay for HBsAg on the cell surface using HBsAg producing hepatocellular carcinoma cell lines and fibroblasts transfected with cloned hepatitis B virus DNA as models. The assay is sensitive, specific, simple and takes approximately 1 1/2 h. The procedure may be modified to compare quantitatively cell surface with intracellular HBsAg and to demonstrate other cell associated hepatitis B virus antigens such as HBcAg and HBeAg.

Mutation analysis of transforming growth factor beta type II receptor, Smad2, and Smad4 in hepatocellular carcinoma.

Mutations in the transforming growth factor beta type II receptor (TGFbetaRII), Smad2, and Smad4 genes have been detected in several human cancers. However, there are no reports of mutation analysis of the entire coding regions in these genes in hepatocellular carcinoma, and the roles of these genes in hepatocarcinogenesis remain unknown. We screened 30 hepatocellular carcinomas for mutations of these genes using polymerase chain reaction single-strand conformation polymorphism. We detected no mutations, but did find 3 cases of loss of heterozygosity of chromosome 17p13.1. These results suggest that mutations of the TGFbetaRII, Smad2, and Smad4 genes are rare, and that genetic instability is uncommon in human hepatocellular carcinoma.

Low MIB-1 labeling index in anti-HCV positive hepatocellular carcinoma.

It has been reported that hepatitis C virus-related hepatocellular carcinoma (HCC) patients survive longer than hepatitis B virus-related patients. In this study, since HCC patients positive for anti-HCV antibody had significantly longer disease-free survival (p<0.05), we evaluated the proliferative activity of 58 resected HCCs and the status of their viral infections. Ki-67 (MIB-1) immunostaining, argyrophilic nucleolar organizer regions and c-myc gene amplification were examined as parameters of proliferation, and p53 overexpression was examined in relation to clinicopathologic features and prognosis. Thirty-nine patients with HCC (67%) were positive for anti-HCV antibody alone, five (9%) were negative for both anti-HCV and HBV antibodies, two (3%) were positive for both anti-HCV and HBV antibodies, and 12 (21%) had HBsAg alone. HCC patients with anti-HCV antibody had a lower MIB-1 labeling index (LI) than HCC patients negative for the antibody (p<0.05), irrespective of the serum HBsAg status. However, there was no significant correlation between anti-HCV antibody and other proliferative parameters. MIB-1 could simply be related to cellular proliferation. On the other hand, the other parameters may be related to tumor progression as well as proliferation. HCV-related HCC does have lower proliferative activity and a better prognosis.

Genetic classification of combined hepatocellular-cholangiocarcinoma.

Combined hepatocellular-cholangiocarcinoma (combined HCC/ CC) is a rare form of liver neoplasms showing both hepatocellular (HCC) and bile duct differentiation (CC). In an attempt to clarify the clonality and genetic/phenotypic relationships in the evolution of these neoplasms, we microdissected multiple HCC and CC foci and studied allelic status of chromosome arms 1p, 1q, 3p, 4q, 5q, 6q, 8p, 9p, 10q, 11q, 13q, 16q, 17p, 17q, 18q, and 22q. Overall, the highest frequency of loss of heterozygosity (LOH) was seen on 4q and 17p, followed by 8p and 16q. Of the 11 cases studied, 3 cases did not show any of the identical allelic losses between HCC and CC foci, indicating the biclonal nature. The remaining 8 cases showed multiple allelic losses shared between both components, strongly suggestive of a single clonal derivation. Moreover, 4 of the 8 cases showed additional or divergent allelic losses at more than 1 chromosomal locus only in HCC and/or CC foci. Thus, this heterogeneity was shown to affect the phenotypic diversity of the tumor. Summarizing the genetic patterns, combined HCC/CC could be classified into the following 3 possibilities: (1) collision tumor in which 2 independent neoplastic clones develop at close proximity; (2) single clonal tumor with homogeneous genetic background in both components--histological diversity is thus a manifestation of divergent differentiation potential of a single clone; (3) single clonal process in which genetic heterogeneity in the process of clonal evolution within the tumor parallels histologic diversity; therefore, the tumor in this category is mainly composed of mosaics of closely related subclones.

Differential distribution of mRNAs encoding phosphatidylinositol transfer proteins alpha and beta in the central nervous system of the rat.

The expression of the alpha and beta isoforms of phosphatidylinositol transfer protein (PI-TP alpha and PI-TP beta) in the adult rat brain was examined by in situ hybridization analysis with isoform-specific RNA probes. PI-TP alpha mRNA was detected in rather restricted regions of the brain whereas PI-TP beta mRNA was widely distributed in the brain. PI-TP alpha mRNA signals were remarkable in neocortex layers II/III and V/VI, Purkinje cell layer, deep cerebellar nuclei of the cerebellum, red nucleus and most part of brain stem. Low levels of PI-TP alpha transcript were present in CA3 of the hippocampus, ventral and dorsal thalamic nuclei, and motoneurons of spinal cord. No hybridization signals was obtained in the olfactory bulb, basal ganglia, amygdala, hypothalamus, and pituitary gland. In contrast, strong signals of PI-TP beta mRNA were detected in the dentate gyrus. The beta isoform mRNA was moderately expressed in olfactory bulb, layers II/III of the neocortex, striatum, CA1-CA4 regions of the hippocampus, medial habenula, cerebellum, amygdala, hypothalamus, spinal cord, and pituitary gland. Thalamus and brain stem contained relatively low, but significant levels of PI-TP beta transcript. The distinct distribution of PI-TP alpha and PI-TP beta mRNAs suggests different functional roles for each of the gene products in the mature nervous system.

Placental metastasis from maternal primitive neuroectodermal tumor.

The occurrence of placental metastasis from maternal primitive neuroectodermal tumor (PNET) is extremely rare. A 33-year-old woman at 33 weeks' gestation was admitted to the hospital. She died of the disease on hospital day 28 because the unresectable tumor was located over a wide area of the retroperitoneum. A neonate was delivered by a caesarean section without evidence of disease and has survived to 1 year of age. Pathologically, the tumor consisted of monotonous small round cells with a high nuclear cytoplasmic ratio, including several pseudorosettes and Homer-Wright-type rosettes. On immunohistochemical examination, the tumor cells were positively stained for neuron-specific enolase. Microscopically, the placenta showed intervillous metastasis from the maternal PNET. This case may be the first one of placental metastasis from PNET ever reported in the literature.

Creatine phosphokinase-linked immunoglobulin associated with hypokalemic myopathy.

We present three women with hypokalemic myopathy in whom serum creatine phosphokinase (CPK) was bound to serum immunoglobulin (macro-CPK). In all three cases, CPK isozyme electrophoresis demonstrated an extra CPK band between CPK-MM and CPK-MB. The bound immunoglobulins were identified as IgA/A-kappa and lambda, IgA-lambda and IgA-kappa and lambda, respectively. In all cases, histological examination of the biopsied muscles revealed necrotic and/or regenerating fibers. In each patient, potassium replacement therapy returned the macro-CPK as well as the marked elevations of serum muscle enzymes to normal. Taken together with other recent reports, our findings suggested that CPK-immunoglobulin binding may be related to the emergence of pathophysiology of hypokalemic myopathy.

Primary omental liposarcoma presenting with torsion: a case report.

An 83 year-old man was admitted because of abdominal pain and distention. A mass measuring 20x10 cm and associated with tenderness and guarding was palpable in the right lower abdomen. Ultrasonography and computed tomography showed a tumor with solid and multiple cystic areas. Celiac angiography showed slight tumor vascularity fed by the right gastroepiploic artery. A malignant tumor of the omentum was suspected. At laparotomy, torsion of the omental pedicle of the tumor was found. Histological examination of the resected tumor revealed characteristics of round-cell liposarcoma, which usually has a poor prognosis. The patient has been alive and well for 2 years. Primary liposarcoma of the omentum has been reported in only seven previous cases. None of these patients presented with torsion, and no report has thus far included a documented survival.

Metastasis and invasion of hepatocellular carcinoma mimicking a right adrenal tumor.

A 60-year-old man presented with a large right adrenal mass. Adrenal primary carcinoma invading the liver and retrohepatic inferior vena cava was suspected after preoperative imagings, which included ultrasonography, computed tomography, selective hepatic and adrenal angiography, and magnetic resonance imaging. An en bloc resection of the right kidney, right adrenal gland, posterior hepatic segment, and laterodorsal of the vena cava was performed using an active veno-venous bypass. The defect of the inferior vena cava was closed using a 6 x 10 cm patch of horse pericardium. The cut surface of the resected specimens revealed a smaller necrotic intrahepatic tumor as well as a large extrahepatic tumor which involved the right adrenal gland and extended continuously to the liver, mimicking an adrenal tumor. As the histological features of the two tumors disclosed the same moderately differentiated hepatocellular carcinoma with a trabecular or pseudoglandular pattern, a huge mass of the right adrenal gland with invasion into the right lobe of the liver, which mimicked a primary adrenal tumor, was diagnosed as metastatic hepatocellular carcinoma from a primary hepatic tumor.

A possible mechanism of primary ciliary dyskinesia: a case of a segmental defect in ciliary microtubules.

We report here a 13-year-old woman with cough, sputum and fever. The patient had both chronic sinusitis and bronchitis. Chest X-ray and computed tomographic scan of the chest revealed mucous bronchial filling and bronchiectasia in bronchi of bilateral lower lobes, right middle lobe and left upper lobe. Aerosol inhalation scintigraphy with 99mTechnetium demonstrated delays of the discharged tracer. On the basis of these findings, primary ciliary dyskinesia was suggested. This was confirmed by the findings from nasal biopsy with transmission electron microscopy where all of the microtubules were segmentally defected near the basal body in the cilia. On the basis of these findings, we diagnosed the patient with primary ciliary dyskinesia which may be due, at least in part, to segmental defect of ciliary microtubules.

Gallbladder carcinoma with choledochoduodenal fistula: a case report with surgical treatment.

A 79 year-old man was admitted to our hospital because of upper abdominal pain and nausea. A mobile tumor was palpable in the right upper abdomen. Abdominal ultrasonography, computed tomography and celiac angiography revealed a gallbladder tumor. Endoscopic retrograde cholangiopancreatography revealed a fistula 1.5 cm oral to the orifice of the papilla of Vater, dilatation of the common bile duct, and a filling defect in the gallbladder. Pancreatoduodenectomy associated with reconstruction using Imanaga's method was performed under a pre-operative diagnosis of gallbladder carcinoma with choledochoduodenal fistula. The gallbladder contained a tumor and two bilirubin stones impacted in the orifice of the duodenal papilla. Histological studies confirmed that the gallbladder tumor was a mucinous adenocarcinoma and had not infiltrated the bile duct. We speculated that choledochoduodenal fistula stimulated the development of cancer due to chronic irritation from pancreatic juice reflux.

Effect of alpha-tocopherol on hepatocarcinogenesis in transforming growth factor-alpha (TGF-alpha) transgenic mice treated with diethylnitrosamine.

To examine the potentially chemopreventive effects of alpha-tocopherol on hepatocarcinogenesis, we fed the transgenic mice line MT42, which overexpresses transforming growth factor-alpha (TGF-alpha) and which has been established as having a high incidence of liver tumor, with different concentrations of alpha-tocopherol and examined the hepatic tumorigenesis of these mice. At 3 weeks of age, MT42 male mice received a single intraperitoneal injection of diethylnitrosamine (DEN), 5 mg/kg body weight, to initiate the formation of liver tumors. The mice were divided into three groups: group A, control diet (20 mg/kg of alpha-tocopherylacetate); group B, deficient diet (less than 1 mg/kg); group C, supplemented diet (500 mg/kg). Neoplastic change was determined at 40 weeks of age. The incidence of adenomas (p < 0.05), the maximum tumor size (p < 0.01), the mean relative liver weight (p < 0.01), and the proliferating cell nuclear antigen (PCNA) labeling indices of the non-tumor sites (p < 0.01) of group B were significantly higher than those of group C. No toxic effects of alpha-tocopherol were found. Alpha-tocopherol-deficient diet accelerated the hepatocarcinogenesis of TGF-alpha transgenic mice treated with DEN. At best, these data demonstrate that alpha-tocopherol-deficiency is not beneficial for prevention of hepatocarcinogenesis in this model. Alpha-tocopherol may be useful for the chemoprevention for liver cancer.

Secondary malignant fibrous histiocytoma following radiation therapy for carcinoma of the uterine cervix: report of two cases.

Two cases of secondary malignant fibrous histiocytoma (MFH) following radiation therapy for uterine cervical cancer are reported. The first case, a 48-year-old woman with a stage IB squamous cell carcinoma of the uterine cervix, underwent a radical hysterectomy with pelvic lymphadenectomy and postoperative radiation therapy. Five years later, she had a poorly differentiated MFH that originated in the right gluteal muscle and lung metastases. The right gluteal tumor and lung metastases were treated with radiation therapy and two courses of cisplatin and etoposide-based chemotherapy. One year after treatment the patient died of multiple pulmonary metastases, although there was no evidence of recurrence in the irradiated field. The second case, a 39-year-old woman with a stage IIB squamous cell carcinoma of the uterine cervix underwent radiation therapy alone. Eighteen years later, well differentiated MFH occurred in the right gluteal muscle with pain on elevation. External radiation therapy was performed because the tumor invaded widely to the right gluteal muscle and pelvic bone. Although the right gluteal pain improved, the tumor showed poor response to radiation. Ten months after treatment, the patient died of multiple pulmonary metastases. These two cases of postirradiation MFH demonstrated different responses to radiation.

Adult embryonal rhabdomyosarcoma showing marked response to radiotherapy: a case report.

A case of embryonal rhabdomyosarcoma (RMS) arising from adult lower proximal extremity is described. Rhabdomyosarcoma (RMS) is most common among children, but adult embryonal RMS is rare. The patient was a 44-year-old man with a large tumor of the left extremity invading to the pelvis. The histological diagnosis was embryonal RMS. Radiation therapy was delivered a total dose of 50 Gy to the tumor. Although adult RMS, usually pleomorphic type, is considered to be radioresistant, the tumor showed marked response to radiotherapy and local control was achieved easily in this case.