Infantile hepatic hemangioma misdiagnosed by prenatal ultrasonography: A case report.

RATIONALE: The drastic differences in treatment and prognosis of infantile hepatic hemangioma (IHH) and hepatoblastoma (HBL) make accurate prenatal diagnosis imperative. The retrospective comparisons of ultrasonic features between fetal IHH and HBL have been reported before, but clinically, the differential diagnosis in utero is very difficult and can lead to prenatal misdiagnosis. PATIENT CONCERNS: A 27-year-old woman at 30 gestational weeks underwent the routine prenatal examination. A heterogeneous solid mass of the fetus, with close relationship to the liver, was recognized by ultrasound. DIAGNOSIS: A diagnosis of HBL was highly considered. INTERVENTIONS: The fetus was aborted and the autopsy was performed. OUTCOMES: The histological outcome was IHH. LESSONS: The prognosis of fetal IHH and HBL is very different, so an accurate diagnosis prenatally is crucial and indispensable. The radiologist and clinician should differentiate between IHH and HBL, especially since the fetus can have serious complications.

The protein kinase activity of fructokinase A specifies the antioxidant responses of tumor cells by phosphorylating p62.

Cancer cells often encounter oxidative stress. However, it is unclear whether normal and cancer cells differentially respond to oxidative stress. Here, we demonstrated that under oxidative stress, hepatocellular carcinoma (HCC) cells exhibit increased antioxidative response and survival rates compared to normal hepatocytes. Oxidative stimulation induces HCC-specifically expressed fructokinase A (KHK-A) phosphorylation at S80 by 5'-adenosine monophosphate-activated protein kinase. KHK-A in turn acts as a protein kinase to phosphorylate p62 at S28, thereby blocking p62 ubiquitination and enhancing p62's aggregation with Keap1 and Nrf2 activation. Activated Nrf2 promotes expression of genes involved in reactive oxygen species reduction, cell survival, and HCC development in mice. In addition, phosphorylation of KHK-A S80 and p62 S28 and nuclear accumulation of Nrf2 are positively correlated in human HCC specimens and with poor prognosis of patients with HCC. These findings underscore the role of the protein kinase activity of KHK-A in antioxidative stress and HCC development.

Huge fetal hepatic Hemangioma: prenatal diagnosis on ultrasound and prognosis.

BACKGROUND: Although huge fetal hepatic hemangiomas are rare, they can cause fatal complications. The purpose of this study is to describe the imaging features and prognosis of these tumors. METHODS: Imaging data were collected for 6 patients with huge fetal hepatic hemangiomas treated at our hospital. Imaging modalities included prenatal magnetic resonance imaging and ultrasound and postnatal color Doppler ultrasound and contrast-enhanced computed tomography (CT). RESULTS: Among the 93,562 fetuses of 92,126 pregnant women examined at our hospital, 6 had huge hepatic hemangiomas (incidence rate, 0.64/10,000), as confirmed via postnatal color Doppler imaging and contrast-enhanced CT. Five fetuses had solitary lesions, whereas 1 (fetus 2) had multiple lesions. Four fetuses had lesions in the right liver lobe and 1 had a lesion in the left liver lobe, and 1 (fetus 2) had lesions in both lobes. All lesions showed centripetal enhancement on postnatal contrast-enhanced CT, which was more intense peripherally. Following postnatal treatment with oral propranolol, with or without dexamethasone or interventional therapy with the medical sclerosant pingyangmycin, all lesions decreased in size, with calcification plaques appearing 6 months after treatment. CONCLUSIONS: Huge hepatic hemangiomas have typical ultrasonographic features and can be diagnosed prenatally. Treatment with propranolol, with or without dexamethasone, may result in a favorable prognosis.

Metastatic neuroblastoma diagnosed on prenatal sonographic examination performed for decreased fetal movement.

We report a case of fetal neuroblastoma presenting with massive liver metastasis diagnosed during the biophysical profile sonographic examination performed for decreased fetal movement. The patient presented at 37 weeks' gestation with limited fetal movement over 24 hours. Biophysical profile showed marked polyhydramnios and an enlarged abdomen filled with a homogeneous mass lesion suspicious for liver metastasis. Primary urgent cesarean section was performed revealing a cachectic neonate with a rigid and grossly distended abdomen. Neonatal evaluation confirmed the etiology of the abdominal mass to be liver metastasis from neuroblastoma. The child died on the 46th day. © 2017 Wiley Periodicals, Inc. J Clin Ultrasound 45:502-506, 2017.

Diagnostic Imaging of Fetal and Neonatal Abdominal and Soft Tissue Tumors.

Imaging plays a key role in the diagnosis and staging of prenatal and neonatal tumors, and is essential in treatment planning. Though obstetrical ultrasound is the first choice prenatally, fetal MRI continues to play an increasing role as experience with this imaging modality increases. In the neonate, in addition to ultrasound and MRI, CT and nuclear medicine studies can also play an important role. We describe the prenatal and neonatal imaging findings of some of the most common congenital abdominal and soft tissue neoplasms including neuroblastoma, renal, liver and soft tissue tumors.

Cancer risks among patients with type 2 diabetes: a 10-year follow-up study of a nationwide population-based cohort in Taiwan.

BACKGROUND: This study aims to determine cancer risks among patients with type 2 diabetes through a follow-up study on a nationwide population-based cohort that included Taiwanese diabetic patients and general population in Taiwan as well as to estimate the population attributable fraction (PAF) of site-specific cancer risks that can be attributed to type 2 diabetes in Taiwanese population by using standardized incidence ratios (SIRs, 95% CI). METHODS: Subjects with type 2 diabetes consisted of 472,979 patients aged ≥ 20 years, whereas general population consisted of 9,411,249 individuals of the same age limit but are not diabetic. Subjects were identified from 1997 to 1998 and followed up until December 31, 2007 or until the first manifestation of any cancer. RESULTS: Cancer sites with increased risks in men, which were consistent with the main and sensitivity analyses, included pancreas (SIR=1.62; 95% CI=1.53 to 1.72), liver (1.61; 1.57 to 1.64), kidney (1.32; 1.25 to 1.40), oral (1.16, 1.12 to 1.21), and colorectal (1.19, 1.15 to 1.22). Cancer sites with increased risks in women included liver (1.55; 1.51 to 1.60), pancreas (1.44; 1.34 to 1.55), kidney (1.38; 1.30 to 1.46), endometrium (1.36; 1.26 to 1.47), bladder (1.19; 1.11 to 1.27), colorectal (1.16; 1.13 to 1.20), and breast (1.14; 1.09 to 1.18). Overall, PAFs were highest for liver cancer in men (4.0%) and women (3.7%), followed by pancreas (3.4%) and kidney (1.6%) cancers in men, and then for endometrium (1.8%) and kidney (1.8%) cancers in women. CONCLUSION: Our data suggested that increased cancer risks are associated with type 2 diabetes.

Involvement of hepatocellular carcinoma biomarker, cyclase-associated protein 2 in zebrafish body development and cancer progression.

Cyclase-associated protein 2 (CAP2) is a conserved protein that is found up-regulated in hepatocellular carcinoma (HCC). By using zebrafish, combined with HCC cell lines, we further investigated the role of CAP2. The zebrafish CAP2 sequence was 60% identical to human CAP2 with 77% homology in the C-terminal actin-binding domain, and 58% in the N-terminal cyclase-binding domain. CAP2 expression was observed during zebrafish development and was preferentially expressed in the skeletal muscle and heart. Knockdown using two different morpholinos against CAP2 resulted in a short-body morphant zebrafish phenotype with pericardial edema. CAP2 was observed co-localized with actin in zebrafish skeletal muscle, and in the leading edge of lamellipodium in HCC cell lines. CAP2 silencing resulted in a defect in lamellipodium formation and decreased cell motility in HCC cell lines. Strongly positive expression of CAP2 was observed in 10 of 16 (63%) poorly, 30 of 68 (44%) moderately, and 2 of 21 (10%) well differentiated HCC. CAP2 expression was significantly associated with tumor size, poor differentiation, portal vein invasion, and intrahepatic metastasis. Our results indicate that an important conserved function of CAP2 in higher vertebrates may be associated with the process of skeletal muscle development. CAP2 also played an important role in enhancing cell motility, which may promote a more invasive behavior in the progression of HCC. These findings highlight the link between development and cancer.

Mucinous cystadenomas in liver: management and origin.

BACKGROUND: Mucinous cystadenomas of the liver are rare cystic neoplasms. The aim of this study was to assess management of a consecutive series of patients who underwent laparotomy for a suspected cystadenoma or cystadenocarcinoma. Secondly, the origin of ovarian stroma (OS) in mucinous liver cystadenomas was examined during early embryonic development. PATIENTS AND METHODS: Patients diagnosed with mucinous liver cystadenomas or cystadenocarcinoma between 1994 and 2009 were included. Pathology specimens of patients who had undergone resection were reviewed for OS. Furthermore, in human embryos, morphology of the peritoneal epithelium and the position of the gonads in relation to the embryonic liver, pancreas and spleen were examined. RESULTS: 15 surgically treated patients (13 female, 2 male) with hepatic tumors were eventually diagnosed with mucinous liver cystadenomas (12) or cystadenocarcinomas (3). OS was present in all female patients with mucinous cystadenoma or cystadenocarcinoma. The 2 male patients were rediagnosed as intraductal papillary mucinous neoplasm (IPMN) or cystadenocarcinoma with features of IPMN. In human embryos, preceding their 'descent', the gonads are situated directly under the diaphragm, dorsal to the liver, the tail of the pancreas and the spleen, but separated from these organs by the peritoneal cavity. In contrast to the peritoneal epithelium elsewhere, the cells covering the gonads show an activated morphology. CONCLUSION: For the diagnosis of mucinous liver cystadenoma, the presence of OS is prerequisite. This may be explained by the common origin of cystadenoma and OS in epithelial cells that cover the embryonic gonads in early fetal life.

Claudin-1 and claudin-2 differentiate fetal and embryonal components in human hepatoblastoma.

Claudins (CLDNs), a family of transmembrane proteins, are major constituents of tight junctions (TJs). They have been shown to be differentially regulated in malignant tumors and play a role in carcinogenesis and progression. We aimed to explain the molecular mechanism underlying the main epithelial components of hepatoblastomas (HBs) based on the composition of TJs. Fourteen formalin-fixed, paraffin-embedded surgical resection specimens were analyzed by immunohistochemistry for CLDN-1, -2, -3, -4, -7; proliferating cell nuclear antigen (PCNA); Ki-67; beta-catenin; cytokeratin-7 (CK-7); and hepatocyte-specific antigen; messenger RNA was isolated for real-time reverse transcriptase polymerase chain reaction analysis of the CLDNs from dissected fetal and embryonal cell types. Significantly increased protein and messenger RNA expression of CLDN-1 and -2 was detected in the fetal compared with the embryonal component. Both cell types displayed negative or weak immunostainings for CLDN-3, -4, and -7. Hepatocyte-specific antigen was dominantly expressed in the fetal component. PCNA and Ki-67 labeling indices were significantly higher in embryonal compared with fetal cells. beta-catenin cytoplasmic/nuclear immunoreaction was frequent, although not showing significant differences between fetal and embryonal cells. Mutational analysis of beta-catenin detected mutation in two cases. Our results suggest that increased expression of CLDN-1 and -2 characterizes the more differentiated fetal component in HBs and is a reliable marker for differentiating fetal and embryonal cell types in HBs. The results proved that the embryonal and fetal components of HBs differ in such important feature as the protein composition of TJs. The expression of CLDN-1 and -2 is inversely correlated with cell proliferation. The more aggressive, rapidly proliferating embryonal phenotype is associated with the decrease/loss of CLDN-1 and -2. However, there are no data indicating association with the nuclear translocation of beta-catenin.

Wnt/Frizzled signaling in hepatocellular carcinoma.

The Wnt/Frizzled (FZD) signaling cascade is important for cell fate determination during embryonic development as well as maintaining tissue homeostasis in the adult. In addition to these physiologic roles, studies have shown that deregulation of Wnt/FZD signaling occurs during carcinogenesis. As an example, over 90% of the colorectal cancers have mutations in adenomatous polyposis coli (APC) or beta-catenin genes. In addition, hepatocellular carcinoma (HCC) is another tumor with frequent aberrant activation of beta-catenin signaling. Nuclear and/or cellular beta-catenin accumulation, a hallmark of the activated canonical Wnt/FZD signaling, has been observed in 33-67% of tumors. However, mutations of APC and/or beta-catenin genes are found only in about 20-30% of HCCs, suggesting that the predominant mechanism(s) activating Wnt/FZD signaling pathway may be different from that found in colorectal cancers. There is accumulating evidence to suggest that regulatory mechanisms other than mutations involving beta-catenin or proteins in its destruction complex, many of which involve upstream components of the Wnt/FZD cascade, are important in HCC. Furthermore, information on the target genes of Wnt/FZD signaling and their roles in hepatocarcinogenesis is limited despite the recent discovery of several candidate genes. This review focuses on the alterations of Wnt/FZD signaling pathways and their relationship to the pathogenesis of HCC. A better understanding of the precise mechanisms of altered Wnt/FZD signaling may provide new molecular targets for therapy of HCC.

[Cystadenomas with ovarian stroma in liver and pancreas: indications of embryonic migration of the gonadal epithelium]. / Cystadenomen met ovarieel stroma in lever en pancreas: aanwijzingen voor embryonale migratie van gonadaal epitheel.

OBJECTIVE: To provide an embryological explanation for the presence of ovarian stroma in cystadenomas of the liver and pancreas. DESIGN: Investigation of patients and embryos. METHOD: From 1997 to 2001 in the Academic Medical Centre, Amsterdam, the Netherlands, nine women were treated for a cystadenoma with ovarian stroma, six of which were situated in the liver and three in the tail of pancreas. In one patient with a cystadenoma in the liver, malignant changes had taken place. In embryos at 5-8 weeks development, the regional differences in the morphology of the epithelium of the peritoneal cavity and the position of the gonads in relation to the embryonic liver, pancreas and spleen were examined. RESULTS: In the foetal period before the gonads begin to descend, they are situated directly dorsal to the liver, tail of pancreas and spleen, but are separated from these by the peritoneal cavity. The cells that cover the urogenital folds distinguish themselves from those elsewhere in the peritoneal cavity as they are bulging in shape as opposed to flattened. This activated morphology suggests that on physical contact with a neighbouring organ the cells covering the gonads may become detached and lodge in that organ. CONCLUSION: It is likely that cystadenomas of the liver and pancreas have their origin in the cells that cover the embryonic gonads. The anomalous morphology of these covering cells in fact suggests that they are relatively easily mobilized. They are probably comparable with inoculation metastasis in the coelomic cavity. Taking the chance of malignant transformation of a cystadenoma into account, the treatment of choice is radical resection of the abnormality.

Fetal mesenchymal hamartoma of the liver: report of a case.

The authors report a case of hepatic mesenchymal hamartoma diagnosed prenatally with ultrasound scan and magnetic resonance imaging (MRI) and confirmed histologically postdelivery. The fetus had a multicystic mass in the left upper abdomen, which showed a rapid enlargement accompanying maternal hypertension and preterm labor. The patient was delivered by cesarian section at 30 weeks and 5 days weighing 1,190 g, and, at birth, a large abdominal mass and severe anemia were noted. Surgical resection and neonatal management were successful, and the patient is alive in a good condition after 3 years follow-up. Although histologically benign, because this lesion frequently results in perinatal complications such as fetal hydrops, maternal toxemia, and preterm labor, early careful fetal ultrasonography should improve the prognosis of this lesion.

Immature hepatic tumor of bimodal differentiation in a young adult patient: a novel lesion expressing beta-catenin and mimicking a distinct phase of hepatogenesis.

PATIENT AND METHODS: A large right-sided liver tumor was incidentally discovered and totally resected in a 21-year-old female patient without chronic liver disease. Histopathologic examination revealed that this malignant tumor does not fit any of the known types of primary liver tumors reported thus far. RESULTS: The lesion chiefly consisted of numerous solid nests composed of immature epithelial cells disclosing a marker profile typical for hepatocytes and strongly expressing beta-catenin. These nests were tightly associated with abnormal duct-like profiles exhibiting features of bile duct cells. CONCLUSIONS: The finding of numerous neoplastic hepatobiliary units ('liverlets') suggests that this tumor may mimic a distinct developmental phase of hepatogenesis close to ductal plate formation.

Activation of beta-catenin in epithelial and mesenchymal hepatoblastomas.

Wnt/beta-catenin signaling is frequently activated in cancer cells by stabilizing mutations of beta-catenin or loss-of-function mutations of the APC tumor suppressor gene. We have analysed the role of beta-catenin in the pathogenesis of hepatoblastoma (HB), an embryonic liver tumor occurring mainly in children under 2 years of age. Sequence analysis of the beta-catenin NH2-terminal domain in 18 epithelial and mixed HBs revealed missense mutations in the GSK3beta phosphorylation motif or interstitial deletions in 12 tumors (67%). In the remaining cases, no truncating mutation of APC could be evidenced. Immunohistochemical analysis of beta-catenin in 11 HBs demonstrated nuclear/cytoplasmic accumulation of the protein in all tumors analysed, with predominant nuclear beta-catenin immunostaining in undifferentiated cells. Membranous beta-catenin localization was preserved only in fetal-type tumoral hepatocytes and was associated with E-cadherin expression. Moreover, we show that beta-catenin is aberrantly overexpressed in a large spectrum of tumor components, including hepatocyte-like cells at various differentiation stages and heterologous elements such as squamous, osteoid and chrondroid tissues, and in occasional other mesenchymally-derived cells. These data strongly suggest that activation of beta-catenin signaling is an obligatory step in HB pathogenesis, and raise the possibility that it interferes with developmental signals that specify different tissue types at early stages of hepatic differentiation.

Anatomic basis of hepatic surgery.

Modern hepatic surgery is based on precise anatomic foundations. The importance of this information applies to all levels of the diagnostic and therapeutic chain. Modern methods of imaging--CT scanning, MR imaging, and preoperative sonography--help physicians to detect variations and plan surgical excision.

Carcinogenic alterations in murine liver, lung, and uterine tumors induced by in utero exposure to ionizing radiation.

The atomic bombing of Hiroshima and Nagasaki and the nuclear accident at Chernobyl raised the question of prenatal sensitivity to ionizing radiation-induced cancer. In this study, mice were exposed to single doses of gamma-radiation (0.2-2.0 Gy) at different embryonic stages. The tumor incidence increased with dose from 15% in control mice to 35% in mice irradiated with 2.0 Gy on 18 d of prenatal life. Various oncogenic events were investigated in lymphoid, liver, lung, and uterine tumors. We observed threefold to fivefold increases in myc expression in 25% of the lymphomas, and the expression of Ha-ras and p53 genes decreased in 40% and 60% of the lung tumors by twofold to fivefold. Point mutations were tissue specific: Ha-ras codon 61 mutations were found in about 40% of the liver adenocarcinomas, Ki-ras codon 12 mutations in about 17% of lung tumors, and p53 mutations in about 15% of the lymphomas. Amplification and rearrangement of the p53, myc, and Ha-, Ki- and N-ras genes were not detected. Loss of heterozygosity on chromosome 4 at the multiple tumor suppressor 1 and 2 genes was observed in all types of malignancies. Allelic losses on chromosome 11 at the p53 locus were found in lymphoid, liver, and lung tumors, but they were absent from uterine tumors. Multiple oncogenic changes were often detected. The frequency of carcinogenic alterations was similar in spontaneous and radiation-induced lymphoid, liver, and uterine tumors. In radiation-induced lung adenocarcinomas, however, the incidences of many oncogenic changes were different from those found in their spontaneous counterparts. This suggests that different oncogenic pathways are activated during spontaneous and in utero gamma-radiation-induced murine lung carcinogenesis.

Hepatoma-derived integrated HBV DNA causes multi-stage transformation in vitro.

The hepatoma-derived hepatitis B virus (HBV) DNA insert HU-a has recently been shown to contain two viral transactivator genes, X and preS2 /S. We report here that HU-a induces malignant transformation after stable transfection of the fetal mouse hepatocyte line FMH202, as indicated by soft agar growth and nude mouse tumorigenicity. Transfections with HU-a subclones, containing the X gene of the preS2 /S gene alone or sequences without transactivator gene, respectively, suggested that the X gene is essential for transformation. Sequential stages of transformation and tumor progression were analysed by injection of the stably transfected FMH202 lines into nude mice, explanation of the resulting tumors and re-establishment of cell lines from the tumors. Comparison of two HU-a-transformed cell lines by HBV mRNA hybridization, Southern analysis and chromosomal in situ hybridization revealed that integrated HBV DNAs were involved in major chromosomal rearrangements in both cases. Interestingly, recombination of the HBV Dna insert during the nude mouse passage had completely abolished HBV-specific transcription in one case, indicating that expression of integrated HBV genes, while presumably involved in early transformation, is dispensable at later stages of tumor progression. The sequential transformation observed in this experimental system suggests that expression of the X gene by integrated viral DNA and subsequent hepatocyte genome mutations might both contribute to HBV-associated liver carcinogenesis.

Multienzyme control serum (Seraclear-HE) containing human enzymes from established cell lines and other sources. 1: Preparation and properties.

We have developed a new multienzyme control serum, Seraclear-HE, which was designed to function not only as an accuracy and precision control serum but also as an intermethod calibrator for unifying interlaboratory clinical enzyme data in terms of reference method values. Seraclear-HE contains as analytes the following enzymes of human origin only: aspartate aminotransferase (AST, EC 2.6.1.1) and lactate dehydrogenase (LD, EC 1.1.1.27) from erythrocytes; alanine aminotransferase (ALT, EC 2.6.1.2) from a hepatoma cell line; alkaline phosphatase (ALP, EC 3.1.3.1) from an amnion cell line; creatine kinase (CK, EC 2.7.3.2) from an embryo kidney cell line; gamma-glutamyltransferase (GGT, EC 2.3.2.2) from a macrophage cell line; and amylase (AMY, EC 3.2.1.1) from urine and saliva. The seven partly purified enzymes were lyophilized in partially delipidated human serum containing sucrose (50 g/L), pyridoxal 5'-phosphate (30 mmol/L), and other stabilizers. The material is stable for at least 2 years at temperatures < or = 10 degrees C. For two concentrations of this preparation, reference method values (mainly International Federation of Clinical Chemistry and Japan Society of Clinical Chemistry) obtained at both 30 degrees C and 37 degrees C are assigned.