Hepatocellular carcinoma (case 2-1996)
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Carcinoma, Hepatocellular↗
Biomedical subjects
M Werner
Publications and source records attributed to M Werner.
Assessing moderate alcohol consumption as a personal risk factor.
Alcohol consumption has been associated with favorable as well as adverse health effects. Risk factors represent formal predictors that such outcomes will occur more frequently than due to chance alone, but these epidemiological indicators are only average statistical associations, and by themselves do not prove causality. However, the concept of risk factors assumes that the total health hazard for any defined age-sex-race cohort can be segmented into one component accounted for by the effects of specified risks and one component accounted for by the "basic average health hazard". Typically, the risk-outcome relationships of drinking are not linear. A so-called U-shaped association between drinking and total mortality has been proposed, whereby moderate drinkers have lower mortality than either abstainers or heavy drinkers. When the relative risk of drinking is formulated as a quotient (odds ratio) with the basic health hazard used as the denominator, appropriate definition and selection of the reference population used to derive the latter becomes pivotal. Equally crucial is the choice of the yardstick for outcome. To date such objective measures as morbidity or mortality have been used almost exclusively, but the complex impact of drinking would demand assessment of physical, mental and social functioning. Finally, the threshold value above which drinking should be considered epidemiologically significant is a judgmental issue, where ethical bias can express itself. By their very nature epidemiological risk estimates are inadequate if not inapplicable to advise everyone that moderate drinking is a personal medical benefit or risk. To render any health factor identified by statistical relationships applicable in individual medical counselling demands validation by clinical trial of its sensitivity, specificity, predictive values, and associated benefits as well as costs. This information has not been compiled, but nevertheless, epidemiological correlations can be used to compare risks and benefits among different health factors to arrive at informed personal choices.
Alcohol Drinking↗
Standardized medical decisions.
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Chemistry, Clinical↗
Mutations in the alpha-amanitin conserved domain of the largest subunit of yeast RNA polymerase III affect pausing, RNA cleavage and transcriptional transitions.
The alpha-amanitin domain or domain f of the largest subunit of RNA polymerases is one of the most conserved of these enzymes. We have found that the C-terminal part of domain f can be swapped between yeast RNA polymerase II and III. An extensive mutagenesis of domain f of C160, the largest subunit of RNA polymerase III, was carried out to better define its role and understand the mechanism through which C160 participates in transcription. One mutant enzyme, C160-270, showed much reduced transcription of a non-specific template at low DNA concentrations. Abortive synthesis of trinucleotides in a dinucleotide-primed reaction proceeded at roughly wild-type levels, indicating that the mutation did not affect the formation of the first phosphodiester bond, but rather the transition from abortive initiation to processive elongation. In specific transcription assays, on the SUP4 tRNA gene, pausing was extended but the rate of RNA elongation between pause sites was not affected. Finally, the rate of cleavage of nascent RNA transcripts by halted mutant RNA polymerase was increased approximately 10-fold. We propose that the domain f mutation affects the transition between two transcriptional modes, one being adopted during abortive transcription and at pause sites, the other during elongation between pause sites.
Amanitins↗
Diagnostic discrimination and cost effective assay strategy for leukocyte alkaline phosphatase.
Decreased leukocyte alkaline phosphatase (LAP) is a first line test for chronic myelogenous leukemia (CML), generally preceding a diagnostic algorithm which also includes bone marrow biopsy, cytogenetic analysis, and molecular diagnostics. We found the analytical uncertainty of LAP assays to range from over 100% coefficient of variation at low scores to about 20% at high scores. However, the receiver-operator characteristics derived from LAP determinations in 50 consecutive cases suggest that a suitably high diagnostic decision threshold still can eliminate false negatives. As a consequence of such a strategy, as many as half the tested patients, classified unequivocally as the negatives, can avoid further invasive and costly workup. On the other hand, serial LAP determinations, whether performed to detect change to a lower or to a higher score, are unlikely to produce conclusive diagnostic signals exceeding analytical 'noise.'
Alkaline Phosphatase↗
Megakaryocytes carry the fused bcr-abl gene in chronic myeloid leukaemia: a fluorescence in situ hybridization analysis from bone marrow biopsies.
Histological examination of bone marrow biopsies shows that about one-third of chronic myeloid leukaemia (CML) patients exhibit an increase of megakaryocytes. The megakaryocytic predominance may be so striking that differentiation from other chronic myeloproliferative disorders (CMPD) may be difficult in some CML patients. Megakaryocytes in CML are clonal as demonstrated by loss of glucose-6-phosphate dehydrogenase isoenzymes. The Ph translocation, fusing the abl and bcr genes on chromosomes 9 and 22, however, obviously occurs as a second step in tumour development. So far, the Ph translocation has not been assigned explicitly to megakaryocytes. The question is whether the megakaryocytic cell lineage could harbour the bcr/abl fusion in those CML cases with striking proliferation of megakaryocytes but lack this genetic defect in cases with normal or decreased megakaryocyte counts. We therefore performed triple-colour fluorescence in situ hybridization (FISH) for portions of the bcr and abl genes flanking the breakpoint in CML in paraffin sections of CML cases with normal and with increased numbers of megakaryocytes. This method allows identification of the bcr/abl fusion in single, morphologically intact cells, whereas conventional cytogenetics requires lysis and thus destruction of the cell. Among the 21 CML patients examined by FISH, 10 were informative for bcr and abl genes and displayed distinct hybridization signals within nuclei of bone marrow cells. Besides the granulopoietic cells, megakaryocytes of all those patients (4 without and 6 with varying grades of megakaryocytic increase) displayed bcr/abl fusion signals indicative of a Ph translocation. The lack of hybridization signals in the remaining 11 cases indicates that this technique is not of value diagnostically and should be reserved for scientific questions. Positive controls consisted of conventional chromosome preparations from bone marrow aspirates demonstrating the Ph chromosome in all patients examined, and negative controls of paraffin sections of bone marrow biopsies from non-CML patients. These showed no fusion signals in bone marrow cells, including megakaryocytes, using FISH. Our results demonstrate clearly that not only the transforming event but also the Ph translocation leading to the bcr/abl fusion happens prior to the differentiation of the pluripotent stem cell into different myeloid lineages. The megakaryocytic proliferation evident in some CML cases is probably a consequence of the disease progress.
Biopsy↗
Detection of numerical karyotype changes in the giant cells of Hodgkin's lymphomas by a combination of FISH and immunohistochemistry applied to paraffin sections.
Conventional karyotyping of Hodgkin's disease (HD) has until now yielded only limited insight into karyotypic characteristics of this disease. For this reason, fluorescence in situ hybridization (FISH) using alpha-satellite chromosome-specific probes was applied to paraffin sections of HD tumors in order to verify numerical aberrations suggested to be specific for HD in the literature. The FISH technique was combined with immunohistochemical detection of the CD30 antigen to allow easier identification of the Reed-Sternberg and Hodgkin (RS&H) cells. The number of specific FISH signals per nucleus was determined both in CD30-positive RS&H cells as well as in non-malignant "bystander" cells in order to assess differences in the signal distribution. Contrasted with normal lymphoid cells, the tumor cells in HD were found to be polysomic for at least one of the chromosomes analyzed (1,2,4, and 8). The technique described is a reliable method for confirmation of results obtained from conventional cytogenetics, which is especially suited for archival material or samples not containing dividing cells.
Antigens↗
Antigen retrieval, signal amplification and intensification in immunohistochemistry.
In this overview we emphasize new methods of improving immunohistochemical results in formaldehyde-fixed tissue samples. The benefit of heat-induced antigen retrieval in demasking of concealed epitopes is demonstrated. We provide guidance on the influence of heat-induced antigen retrieval in commonly applied monoclonal and polyclonal antibodies. Moreover, we show the promising methods of signal amplification using biotinylated tyramine and signal intensification of diaminobenzidine reaction products by metallic ions.
Animals↗
[Histologic grading of chondrosarcoma. A qualitative and quantitative analysis of 74 cases of the Hamburg bone tumor register].
Chondrosarcomas are frequent malignant bone tumors. Aside from different subtypes, such as dedifferentiated, mesenchymal and clear-cell chondrosarcoma, chondrosarcomas (classical chondrosarcoma) show different grades of differentiation. The borderline between chondroma and classical chondrosarcoma is not clearly defined. The same chondrosarcoma can be graded differently at different institutes. Standardized therapy concepts are currently in preparation. As the Hamburg Bone Tumor Registry is often consulted for chondrogenic tumors, the histological criteria are based on a series of 74 chondrosarcomas recorded there. The emphasis has been laid on a classification which can be used in daily routine and which is reproducible and in agreement with the classifications of other international groups. Grade I chondrosarcomas (50%) can be distinguished only by growth criteria. The nuclei are small and show high chromatin density. Grade II chondrosarcomas (42%) have medium-sized, regular nuclei with loose chromatin structure. The chondrocytes of grade III cases (8%) show polymorphic nuclei. Binucleas forms, the number of mitoses and cellularity all show considerable overlap for all three grades. So far there are no immunohistological and molecular biological methods for reliable differentiation. The therapeutic consequences of the classification into grades are thorough curettage, in the case of grade I tumors, or complete resection, for grade II and III cases. The long-term results, however, need to be confirmed by a larger number of cases. From 1991 to 1995 the method was applied and proved to be easily practicable in daily diagnostic routine. Some 104 cases of classical chondrosarcomas (grade I 53%, grade II 39%, grade III 8%) were analyzed. Two pathologists both assigned the same grade in 90% of cases.
Adult↗
[Morphologic characteristics of chondroblastoma. A retrospective study of 56 cases of the Hamburg bone tumor register].
Representing only about 1% of all primary bone tumors, chondroblastoma constitutes a very rare bone tumor entity. 56 cases of chondroblastoma, that had been collected by the Hamburg Bone Tumor Registry from 1972 to 1995, were examined histologically together with the radiological and clinical findings. In addition immunohistochemistry with antibodies against S 100, PGM1, LCA and the proliferationmarker MIB 1 was performed. The mean age was 20.4 years and male patients being the majority with a gender ratio of 2.7:1. Predominant localisation was the epiphyses of the long bones, although almost 40% of the tumors were located at untypical sites. Usually a well-circumscribed lysis could be seen on plain X-Ray examination, however partial cortical destruction could be observed in one third of the cases. Histologically characteristic was a polygonal cell component with a weblike chonroid matrix, sometimes with a plane-like appearance. 5 cases showed a distinct nuclear polymorphism making a distinction from osteosarcoma difficult. Using immunohistochemistry all tumors except for one showed positive reaction for S 100 protein. Although the histogenesis of chondroblastoma is not completely understood, morphological findings as well as the observed reactivity with the S 100 protein indicate the chondroid origin. No reactivity for PGM 1 (CD 68) or LCA could be detected. All chondroblastoma showed a low rate of proliferation, thereby being distinguishable from high malignant bone tumors. In general chondroblastoma show a benign biological behavior. Different behavior was observed in 2 cases. One relapse located in the pelvis revealed local aggressive growth while in another case in the humerus a malignant transformation had taken place.
Adolescent↗
[P-glycoprotein expression in osteosarcoma].
One of the mechanisms by which multidrug resistance is mediated, is the mdr1 gene product, P-glycooprotein. Immunohistochemistry was performed for 63 osteosarcomas of 54 patients to investigate P-glycoprotein expression using the monoclonal antibody JSB-1. Most of the patients were children or adolescents who had received treatment under the framework of the Cooperative Osteosarcoma Study Group. In addition P-glycoprotein expression was assayed in five growth plates. Of all cases 68.5% stained positive for P-glycoprotein. Cases that had received chemotherapy showed a higher incidence (80.9%) of positive P-glycoprotein immunostaining than cases that had not received chemotherapy (66.6%). No relation could be established between P-glycoprotein expression and the response to chemotherapy, since the majority of P-glycoprotein positive biopsies showed a good response in the surgical specimen after chemotherapy. Furthermore, 42.9% of P-glycoprotein negative biopsies were classified as non-responders in the later surgical specimen. In addition to P-glycoprotein expression in osteosarcomas positive immunostaining was also detected in osteoblasts, osteocytes, osteoclasts as well as in some chondroblasts. The results indicate that P-glycoprotein expression in osteosarcomas also exists prior to chemotherapy and resembles the phenotype of normal bone tissue. However, the determination of P-glycoprotein by using immunohistochemistry in biopsies of osteosarcomas cannot predict the response to chemotherapy.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
[Cell proliferation in bone tumors. Immunohistologic study of Ki-67 protein expression].
Bone tumors represent a group of tumors of various dignity. In spite of this single tumor entities may display strong morphological resemblance to each other which can in turn result in profound difficulties in differential diagnosis. The biological behaviour of a tumor is mainly determined by its rate of proliferation. In this study the rate of proliferation of 64 bone tumors (30 high-grade central osteosarcomas, 6 low-grade osteosarcomas, 8 giant cell tumors, 8 aneurysmatic bone cysts, 5 osteoidosteomas/osteoblastomas, 7 fibrous dysplasias and 5 cases of a myositis ossificans) were analysed. Immunohistochemistry was performed on paraffin-embedded tissue sections using the MIB-1 monoclonal antibody. MIB-1 recognizes the proliferation-associated Ki-67 protein which is expressed during the active phases of the cell cycle but cannot be detected in senescent cells. Among high-grade central osteosarcomas a significantly higher rate of proliferation (average value 30%) was found in comparison with low-grade osteosarcomas and other benign intraosseous bone tumors. This approach proved to be very useful in the distinction between high-grade and low-grade osteosarcomas as well as bone-forming intraosseous tumors. However distinguishing low-grade osteosarcomas from benign bone tumors by determining only the rate of proliferation was not possible, although interestingly, the proliferative rate of myositis ossificans, a purely reactive lesion, was in the range of the values determined for high-grade osteosarcoma.
Biomarkers, Tumor↗
[Solitary bone cysts. Morphologic variation, site, incidence and differential diagnosis].
Analysis of 402 solitary bone cysts demonstrates the wide morphological variation of this cystic lesion with regard to histology and radiology. Aside from metaphyseal location in femur (33%) and humerus (23%), solitary bone cysts are also often located in calcaneus (11%), tibia (11%) and pelvis (10%). Most patients are in the second decade of life. Differentiation between this benign lesion and malignant bone tumors is very important in daily clinical routine. The diagnosis cannot be based solely on radiological findings because of the variation of solitary bone cysts and the special forms, such as calcifying solitary bone cyst. Therefore, exact histological diagnosis is of particular importance.
Adolescent↗
[Spongiosa structure and polyostotic heterogeneity in osteoporosis. Mechanism of bone transformation, morphology, clinical significance].
Osteoporosis is the most frequent generalized bone disease. The clinical expression of postmenopausal osteoporosis is characterized by spontaneous fractures of the vertebral bodies which affect mainly the trabecular bone structure. Thus the morphological bone transformation in osteoporosis is of clinical relevance. The object of this study was to analyze quantitatively and qualitatively the distribution of three-dimensional structure of cancellous bone in the human spine in osteoporosis. Therefore the complete anterior column of the spine and bone biopsies of the iliac crest of 11 autopsy cases with proven osteoporosis and 26 autopsy cases without primary or secondary bone disease were removed. A 1-mm-thick prepared sagittal section through the center of all vertebral bodies was embedded undecalcified in plastic and stained on the surface using a modification of the von Kossa method. This technique allowed combined two- and three-dimensional measurements simultaneously; these included evaluation of trabecular bone volume, trabecular interconnection, trabecular thickness, and trabecular number. The quantitative spine deformity index and qualitative analysis of the trabecular bone structure completed the investigation. The bone loss in osteoporosis is a loss of structure and the loss of whole trabeculae caused by perforations. The age-related decrease of trabecular bone mass is due to the transformation from plates to rods. Patient with osteoporosis show pathologically diminished trabecular bone volume and apparently reduced trabecular interconnection, while trabecular thickness and trabecular number show age-dependent change. The polyostotic heterogeneity in osteoporosis is immense. Neighboring vertebral bodies show differences of up to 100% in bone volume and bone structure. Due to this fact it is impossible to define a threshold for osteoporotic fractures. At the moment the transformation and loss of trabecular bone structure in osteoporosis is assumed to be irreversible; therefore, early prophylaxis is necessary to prevent clinical manifestations of these changes of bone.
Adolescent↗
[Periosteal osteosarcoma. Histologic characteristics, preparation technique, growth pattern and differential diagnosis].
Periosteal osteosarcoma is a distinct bone tumor entity with characteristic morphological features within the group of juxtacortical osteosarcoma. Periosteal osteosarcoma is predominantly located in the long tubular bones, especially in the tibia and femur and is situated on the outer circumference of the tumor-bearing bone (saucerization phenomenon). In contrast to parosteal osteosarcoma, periosteal osteosarcoma is less differentiated and is believed to have a worse prognosis. In this work the histological features are described with predominantly chondroblastic differentiation of 14 cases with periosteal osteosarcoma. A horizontal preparation technique of periosteal osteosarcoma specimens allows comparison with computed tomography and is the optimal method to detect an invasion of the medullary cavity. Further studies are necessary to clarify if neoadjuvant chemotherapy could improve the prognosis of certain patients.
Adolescent↗
[Solitary fibrous tumor of the epicardium].
A giant Solitary Fibrous Tumor (SFT) arising in the pericardium is described. A 53 year old woman was suspected to have a lung tumor and thoracotomy was performed. Intraoperatively the child-head sized mass was found to be localized in the pericardial sac. The histopathological interpretation of a small wedge-biopsy was 'endothelioma of uncertain malignancy' and heart-transplantation was performed two months later. The patient died of postoperative infection. Post mortem examination could exclude tumor rest or metastasis. The explanted heart revealed a large bulk of 2800 grams arising from the epicardium of the left chamber and enveloping the heart without invading the underlying myocardium. The histopathological pattern varied between cell-rich and -poor fibromatous areas and well capillarized endothelioma-like zones. Immunohistochemistry revealed positive reactions with monoclonal antibodies against Vimentin and CD 34 and no reactions against Cytokeratins and Faktor VIII. This pattern was confirmed in 7 SFT's of the pleura from our archives. A second control group of 7 mesotheliomas was positive for cytokeratins and vimentin but not for CD 34 and Faktor VIII. Diagnosis of SFT might be difficult because of its variability in histopathology, sometimes mimicking a hemangiopericytoma or endothelioma. Recent reports of tumor localizations devoiding serosal surfaces illustrate the diagnostic and histogenetic dilemma of this tumor. The differentiation of SFT from mesothelioma and endothelioma can be achieved by immunophenotyping including CD 34.
Antigens, CD34↗
[Comparative DNA cytometric and cytogenetic ploidy determination of chondrosarcoma and osteosarcoma].
10 chondrosarcomas and 10 osteosarcomas were examined using cytogenetics and DNA-image-cytometry. Cytogenetically 6 of 10 chondrosarcomas and 4 of 10 osteosarcomas showed hyperdiploid tumorcells. By DNA-cytometry in 8 of 10 chondrosarcomas and 9 of 10 osteosarcomas hyperdiploid tumorcells resp. hyperdiploid stemlines were detected. This discrepancy reflects an in-vitro-selection depending on the different entities. In 7 aneuploid clones of chondrosarcomas the chromosomal ploidy was calculated using the relative length of the chromosomes and compared with the DNA-ploidy of the native tumor. There was a close relation between both parameters of nuclear DNA-content. The interpretation of cytogenetic results is improved using a combination of karyotypic and DNA-cytometric examination. This is particularly important for the search for relations between numeric chromosomal aberrations and morphological parameters (grading).
Aneuploidy↗
Trisomy 18 in a canine thyroid adenoma.
A canine thyroid adenoma showing trisomy 18 as the sole clonal cytogenetic abnormality (9 of 30 analyzed metaphases) is reported. Because trisomies are a recurrent cytogenetic finding in human benign thyroid tumors as well, it is suggested that the molecular relationship between these trisomies and the development of thyroid tumors can be determined by comparative gene mapping.
Adenoma↗