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T Wiethege

Publications and source records attributed to T Wiethege.

At least 19 recordsLinked to original sources
PubMed2004

[Pathology, classification, and staging of malignant lung tumors].

The histopathogical, immunohistochemical, and genetic characterization of specimens of, mostly advanced, lung tumors that show variable phenotypes in biopsies of just 1-2 mm does not allow conclusions regarding causal factors (e.g., smoking, radon, asbestos etc.) or further progress of the disease. Therapeutical approach and the still unfavorable prognosis remain essentially, as in the last thirty years, to be characterized by TNM and performance status of the individual patient and, to a lesser extent, by the main histological type of tumor. In recent years, our knowledge of the quite variable biology of tumors has been significantly increased by the use of immunohistochemical methods and molecular biology. These methods facilitated an improved qualitative and quantitative characterization of heterogeneously differentiated lung tumors (e.g., neuroendocrine/blastomatoid portions etc.). The detection of genetic alterations of tumor suppressor genes and oncogenes is, at the moment, only of scientific interest. The heterogeneity of tumors is emphasized by results obtained by molecular genetic techniques. A connection between the detected genetic anomalies and histomorphological growth patterns can not be seen. At the present time, the validity of individual findings for a correlation between operability, tumor progress, chemotherapy and prognosis is not sufficiently elucidated by investigations nor secured.

Gene Expression Profiling↗
PubMed2001

Mutational analysis of N-ras, p53, p16INK4a, p14ARF and CDK4 genes in primary human malignant mesotheliomas.

Nineteen specimens from primary human malignant mesotheliomas obtained from 19 patients were screened for activating point mutations in the oncogenes N-ras and CDK4 by combined RFLP-PCR/SSCP analysis. In addition, all tumours were screened for deletions and point mutations in the tumour suppressor genes p53, p16INK4a (CDKN2A) and p14ARF (exon-1beta) by combined multiplex-PCR/SSCP analysis. No mutations were found in N-ras, p53 and CDK4. Three tumours displayed homozygous deletion (co-deletion of exons 1, 2 and 3) of p16INK4a. One of them displayed additional homozygous deletion of p14ARF (exon-1beta). Two silent point mutations and 2 polymorphisms were found in p16INK4a in 3 tumours. Our preliminary data indicate that disarrangement of the Rb1 pathway may be involved in mesothelioma formation.

Adult↗
PubMed2000

Histopathologic findings of lung carcinoma in German uranium miners.

BACKGROUND: This study evaluates the histopathology of lung carcinoma in relation to underground radon exposure. METHODS: Two hundred forty uranium miners of the former Wismut Company in Eastern Germany with histologically or cytologically confirmed primary lung carcinoma were recruited from 3 study clinics between 1991 and 1995. Information on smoking history was obtained by personal interviews, whereas job histories were derived from original payrolls provided by the Wismut Company. Quantitative estimates of occupational radon exposure were based on a job-exposure matrix. RESULTS: Squamous cell carcinoma (SqCC) was the predominant cell type (43%), followed by adenocarcinoma (AC; 26%), small cell lung carcinoma (SCLC; 23%), and other cell types (8%). Nearly all patients were smokers. Time since first occupational exposure was 42 years on average, the mean cumulative radon exposure 506 working level months. Adenocarcinoma appeared to be more likely than both SCLC and SqCC among miners with low cumulative radiation exposure, long time since first exposure, an older age at diagnosis, and among ex- and never-smokers. In current smokers, lung carcinomas developed at a much lower level of radiation exposure than in ex- and never-smokers. The increase in the relative frequency of SCLC and SqCC at the expense of AC with increasing cumulative radiation exposure was more pronounced among ex- and never-smokers and seemed to be masked among current smokers. CONCLUSION: The authors' data suggest that all cell types were associated with radon exposure, but high radiation exposure tended to increase the proportion of SCLC and SqCC.

Adenocarcinoma↗
PubMed2000

Pathology of small-cell lung cancer.

The morphological differentiation between small-cell and non-small-cell lung cancer has great prognostic and therapeutic significance for the patient. Malignant lung tumors are now classified according to the new 1999 WHO/IASLC classification of lung and pleural tumors. The variant of heterogeneously differentiated "combined small-cell carcinoma" can be distinguished from classical small-cell carcinoma, whereas the subtype of "intermediate cell carcinoma" is no longer used. Together with "large-cell neuroendocrine carcinomas" and typical or atypical carcinoid tumors, small-cell lung cancers are currently histogenetically categorized as neuroendocrine lung tumors. In contrast to large-cell neuroendocrine carcinoma, the immunohistochemical demonstration of neuroendocrine differentiation is not a prerequisite for the diagnosis of small-cell lung cancer. Although electron-microscopical, immunohistochemical, and molecular-biological findings have considerably increased our understanding of the pathogenesis and progression of malignant lung tumors, routine pathological-anatomical diagnostics are still decisively based on light-microscopical evaluation of tissue samples.

Carcinoma, Small Cell↗
PubMed2000

[Pathology and molecular biology of lung cancer].

Therapy and prognosis of lung cancer depend crucially on tumor size, tumor stage, and the histomorphological tumor type at the time of primary diagnosis. A tumor weighing only 1 g and barely detectable by clinical examination consists of about 1 x 10(9) tumor cells. The primary histological diagnosis is generally based on small biopsies 1-2 mm in diameter, which allow the assessment of only a few up to some hundred tumor cells in a section of 4 microns. Until 20 years ago light microscopic and histochemical investigations were the basis for sophisticated morphological tumor diagnosis. In recent years electron microscopy, immunohistochemistry, cytometry, and molecular biology have extended our knowledge of the complex tumor biology, with the range of phenotypes and genotypes indicating enormous tumor heterogeneity. The value, expressiveness, and prognostic importance of these laborious and expensive techniques must be examined in studies, keeping in mind new aspects of tumor classification. Histological and cytological findings are still the decisive basis for the primary diagnosis of the pathologist in any given case.

Biopsy↗
PubMed2000

p53 tumour-suppressor gene in non-small-cell lung cancer with neoadjuvant therapy.

In a phase II study for optimizing therapeutic management of locally advanced non-small-cell lung cancer the prognostic and therapeutic relevance of the p53 status was investigated. Biopsy or mediastinoscopy samples, collected prior to neoadjuvant chemoradiotherapy and corresponding resection specimens, were analysed immunohistochemically (CM1 antiserum) for p53 accumulation and molecular biologically (polymerase chain reaction/single-strand conformation polymorphism) for p53 mutations. The results were correlated to the response to therapy (regression grade) and to the survival times. p53 accumulation was found in 41.7% (prior to neoadjuvant therapy) and in 40.0% (after surgery) of the tumours. p53 mutation was demonstrated in 45.4% (prior to neoadjuvant therapy) and in 46.4% (after surgery) of the investigated tumours. Neither before nor after therapy was any correlation to the survival times or to the response to therapy seen in the collective analysed. Thus, such investigations are not suitable for identifying patients with locally advanced non-small-cell lung cancer who might benefit, to different extents, from neoadjuvant therapy.

Adult↗
PubMed2000

Co-expression of vascular endothelial growth factor and its receptor flt-1 in malignant pleural mesothelioma.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a potent angiogenic protein with a selective mitogenic effect on endothelial cells known to be involved in many normal and pathological processes. Coexpression of VEGF and its receptor flt-1 has been reported in different types of malignant tumors. OBJECTIVE: In the present study we investigated the expression of VEGF and flt-1 in 90 cases of diffuse malignant pleural mesotheliomas. METHODS: VEGF and flt-1 expression was analyzed by immunohistochemistry and non-radioactive in situ hybridization. RESULTS: VEGF expression was visualized immunohistochemically in tumor cells. flt-1 expression correlated with histological differentiation (p < 0.013). Furthermore, expression of flt-1 was detected in tumor cells, macrophages and microvessels adjacent to tumor cells. VEGF and flt-1 expression were confirmed by in situ hybridization. CONCLUSION: There was a statistically significant correlation between VEGF and flt-1 expression (p < 0.001). The observed coexpression of VEGF and flt-1 possibly suggests a potential autocrine loop for malignant pleural mesothelioma cells.

Aged↗
PubMed1999

Presence of simian virus 40 sequences in malignant mesotheliomas and mesothelial cell proliferations.

Malignant mesotheliomas (MMs) are pleural-, pericardial-, or peritoneal-based neoplasms usually associated with asbestos exposure. Mesothelial cells are biphasic and may give rise to epithelial and sarcomatous MMs. In addition, benign or atypical proliferations of mesothelial cells may occur in response to many stimuli. There have been recent reports of simian virus 40 (SV40) DNA large T antigen (Tag) sequences in pleural MMs. To further understand the relationship between SV40, MMs, and mesothelial proliferations, we studied 118 MMs from multiple sites in Germany and North America, including 93 epithelial pleural, 14 sarcomatous or mixed pleural MMs, and 11 peritoneal MMs. In 12 pleural MMs, adjacent noninvasive tumor foci were identified and studied separately. Information about asbestos exposure (detailed history and/or microscopic examination for asbestos bodies) was available from 43 German patients. In addition, 13 examples of reactive mesothelium and 20 lung cancers from the United States were tested. DNA was extracted from frozen tumor and adjacent nontumorous tissues or after microdissection of archival formalin-fixed, paraffin-embedded microslides. Two rounds of PCR were performed with primers SVFor 3 and SVRev, which amplify a 105 bp region specific for SV40 Tag. The specificity of the PCR product was confirmed in some cases by sequencing. Our major findings were: 1) Specific SV40 viral sequences were present in 57% of epithelial invasive MMs, of both pleural and peritoneal origin. No significant geographic differences were found, and frozen and paraffin-embedded tissues were equally suitable for analysis. 2) There was no apparent relationship between the presence of SV40 sequences and asbestos exposure. 3) SV40 sequences were present in the surface (noninvasive) components of epithelial MMs. 4) SV40 sequences were not detected in MMs of sarcomatous or mixed histologies. 5) Viral sequences were present in two of 13 samples (15%) of reactive mesothelium. 6) Lung cancers lacked SV40 sequences, as did non-malignant tissues adjacent to MMs. Our findings demonstrate the presence of SV40 sequences in epithelial MMs of pleural and peritoneal origin and their absence in tumors with a sarcomatous component. Viral sequences may be present in reactive and malignant mesothelial cells, but they are absent in adjacent tissues and lung cancers.

Antigens, Polyomavirus Transforming↗
PubMed1999

Expression of vascular endothelial growth factor in diffuse malignant pleural mesothelioma.

Angiogenesis is an important part of normal and pathological processes, including tumour growth, metastasis, inflammation and wound healing. VEGF is the best known angiogenic factor, implicated in tumour-associated microvascular hyperpermeability and carcinogenesis. We investigated 103 malignant pleural mesotheliomas, analysing the expression of vascular endothelial growth factor using immunohistochemistry and in situ hybridization. The grade of microvessel density was assessed with the aid of anti-factor-VIII antibodies. An increased expression of VEGF was found in biphasic and epithelioid mesotheliomas, correlating in a statistically significant manner (P<0.042). In situ hybridization confirmed the specificity of VEGF mRNA expression. There was a robust correlation between VEGF expression and increased microvessel density (P<0.001), and positive mesotheliomas had significantly higher microvessel densities than negative specimens. There was also a significant correlation between microvessel density and histological pattern. As growth pattern tended towards biphasic and sarcomatoid mesotheliomas the density of micovessels decreased (P<0.05).

Adult↗
PubMed1999

German uranium miner study--historical background and available histopathological material.

Mining activities in the former German Democratic Republic were documented as early as 1168 in the ore mountains (Erzgebirge) of Saxony. Silver, bismuth, cobalt, nickel and tungsten were mined from then up to the end of the 19th century. After the Second World War, the Soviet Occupation Authorities reopened the old silver mines in Saxony to mine uranium for the Soviet nuclear industry. About 400, 000 workers produced a total of 220,000 tons of uranium during the years 1946 to 1990. After the reunification of Germany, the archive of the Institute of Pathology of the mining area was opened for research. It contains protocols of 28,975 autopsy cases and about 400,000 slides collected from 1957 to 1992, about 66,000 tissue blocks, and 238 whole lungs. From the autopsy cases, 17,466 could be identified as workers of the uranium mining company. The remainder of the cases were in the population of the mining area. A comparison of the frequencies of malignancies of male workers older than 15 years with those of the population of the mining area for the years 1957 to 1989 demonstrates a significantly higher percentage of lung cancer among the uranium miners. There was no significant difference for other solid cancers and leukemias.

Cause of Death↗
PubMed1999

German uranium miner study--pathological and molecular genetic findings. German Uranium Miner Study, Research Group Pathology.

Uranium miners of the former Wismut company in Germany form the largest cohort of workers exposed to (222)Rn and dust in the world. The German Uranium Miner Study, Research Group Pathology, is evaluating the central pathology archive of the Wismut company. The main tasks of our study are pathological-anatomical and molecular genetic investigations of 28,975 autopsy cases and the evaluation of mining pollutants in the lungs by neutron activation analysis. As part of an observer agreement study, lung tumors are classified according to the WHO/IASLC classification and nontumorigenic lung disorders are registered. Lung tumors were analyzed for the presence of a proposed radon-specific mutation in the TP53 gene (formerly known as p53). Interim results are: (a) In the years 1957 to 1965, a high rate (69%) of small cell carcinomas was found which had declined to 34% by 1990. (b) The percentage of the deceased who suffered from silicosis is not higher in the group of lung tumors than in other tumor groups or the nontumor group. (c) The hypothesis of a radon-characteristic hotspot mutation in the TP53 tumor suppressor gene is not supported by our investigations. (d) Neutron activation analysis demonstrates that uranium, arsenic, chromium, cobalt and antimony can be found in tissue samples from the miners even when they had stopped working more than 20 years before death.

Genes, p53↗
PubMed1998

[Myositis proliferans: a pseudosarcomatous lesion in soft tissue].

Myositis proliferans is a reactive, intramuscular soft tissue disease characterized by fibroblast and myofibroblast proliferation, showing similarities to the phase-like development seen in the general pathology of wound healing and hypertrophic scars. Immunohistochemically, a combined expression of vimentin and alpha-sm actin is seen in the spindle-shaped cell formations. The decisive histological preparations is supported by immunohistochemical techniques, especially in the differentiation from sarcoma. If a definite diagnosis is made, incomplete excision may suffice.

Actins↗
PubMed1998

Expression and localization of vascular endothelial growth factor and its receptor flt in pulmonary sarcoidosis.

Vascular endothelial growth factor (VEGF) is a multifunctional cytokine, which has recently been reported to enhance the activation and migration of monocytes through the flt receptor in vitro, which are key events in granuloma formation of granulomatous disorders and in sarcoidosis. Since activated macrophages and monocytes are known to be involved in sarcoid granuloma formation in sarcoidosis, we investigated the expression of VEGF and its receptor flt in 33 paraffin-embedded lung tissue biopsies of patients with pulmonary sarcoidosis. VEGF-mRNA was localized by nonradioactive in situ hybridization, VEGF and flt expression were visualized immunohistochemically. We found an increased transcription and protein production of VEGF and an overexpression of flt in activated alveolar macrophages, in epitheloid cells, and in multinuclear giant cells of pulmonary sarcoid granulomas.

Adult↗
PubMed1998

Hepatocyte growth factor/scatter factor and its receptor c-Met are overexpressed and associated with an increased microvessel density in malignant pleural mesothelioma.

Hepatocyte growth factor/scatter factor (HGF/SF) stimulates cell proliferation, motility and invasiveness via its receptor c-Met during embryogenesis and repair processes. It induces angiogenesis, promoting endothelial cell migration and capillary-tube formation in vivo. Co-expression of HGF/SF and c-Met receptor results in enhanced tumour growth, invasiveness and a mesenchymal-epithelial transition in some experimental tumours. Since mesothelioma cells have been reported to express c-Met receptor and to migrate in response to HGF/SF, we investigated human malignant pleural mesotheliomas for the demonstration of possible co-expression of the growth factor and its receptor. The microvessel density of the tumours was also analysed in order to assess the influence of HGF/SF expression on tumour angiogenesis. Thirty-nine paraffin-embedded specimens of malignant pleural mesotheliomas were immunostained by anti-HGF/SF and anti-c-Met antibodies and semiquantitatively evaluated. c-Met mRNA expression was visualised in ten tumour samples by a fluorescent in situ hybridisation method. Microvessel density was calculated by counting microvessels with a high-power field (200x) on von-Willebrand-factor-stained slides. We found an increased production of HGF/SF in 33/39 tumours and a corresponding overexpression of c-Met receptor in 29/39 specimens. The FISH method detected increased transcription of c-Met mRNA in malignant cells and in neighbouring vascular endothelial cells. HGF/SF-positive mesotheliomas had significantly higher microvessel densities compared to their HGF/SF-negative counterparts. The observed co-expression of HGF/SF and c-Met in malignant pleural mesotheliomas suggests a possible self-stimulation (autocrine loop) of tumour cells. On the basis of the significantly higher microvessel density values of malignant mesotheliomas overexpressing HGF/SF, we postulate, that HGF/SF may be an additional relevant factor in tumour angiogenesis in malignant pleural mesotheliomas.

Hepatocyte Growth Factor↗
PubMed1997

Expression and localization of thrombomodulin in preneoplastic bronchial lesions and in lung cancer.

Thrombomodulin (TM) is an endothelial surface glycoprotein that acts as a natural anticoagulant. It inhibits thrombin and accelerates the activation of the anticoagulant protein C. TM has been detected in dermal keratinocytes, where it is associated with terminal differentiation. It can also be detected in various types of squamous malignant neoplasms and in malignancies of endothelial and mesothelial origin, such as Kaposi's sarcoma or malignant mesothelioma, but is absent in pulmonary adenocarcinomas (AC). Seventy-two lung tumour specimens [33 squamous cell carcinomas (SQCC), 23 AC, 1 large cell carcinoma, 8 small cell lung cancers (SCLC) and 7 multidifferentiated tumours (MT)] were analysed immunohistochemically by staining with an anti-TM antibody in order to assess TM expression. All of the SQCC stained positively for TM. In contrast, only 9 AC and 4 MT and none of the SCLC showed positive anti-TM staining. Seven hyperplastic bronchial epithelial specimens and eight preneoplastic bronchial lesions (five cases of moderate dysplasia, two cases of severe dysplasia and one case of carcinoma in situ) were used as controls. Normal or hyperplastic areas of bronchial epithelium revealed no positive reaction. However, a distinct positive anti-TM staining pattern related to the degree of keratiniziation of dysplastic lesions was seen. The present results suggest that anti-TM immunostaining is a useful marker for squamous cell carcinoma in the differential diagnosis of pulmonary carcinoma, also indicating keratinocyte differentiation in dysplastic bronchial epithelium.

Adenocarcinoma↗
PubMed1997

Expression of type IV collagenase correlates with the expression of vascular endothelial growth factor in primary non-small cell lung cancer.

Tumor growth and metastasis are angiogenesis-dependent processes initiated and regulated by a number of cytokines. Vascular endothelial growth factor (VEGF) is a potent angiogenic protein with a selective mitogenic effect on vascular endothelial cells, known to be involved in physiological (embryogenesis) and pathophysiological (rheumatoid arthritis, tumor) angiogenesis. An increased expression of matrix metalloproteinase type IV collagenase has been reported in invading endothelial cells in vitro and in malignant cells, degrading structures of the basement membranes in various human malignancies. In the present study we investigated the expression of the genes for type IV collagenase and vascular endothelial growth factor (VEGF) in 40 cases of primary non-small-cell lung cancer (NSCLC). Specimens were immunostained by an antibody directed against VEGF and mRNA transcripts of VEGF and type IV collagenase were localized by non-radioactive in situ hybridization. VEGF mRNA was detected in 33 neoplasms, while in 23 cases transcripts of the type IV collagenase gene were visualized by digoxigenin-labeled cDNA probes. Transcripts of both mRNAs were detected in malignant cells. Furthermore, anti-VEGF immunostaining was present in newly formed microvessels close to the atypical cells, and mRNA of type IV collagenase was present in stromal cells adjacent to the tumor. A statistically significant correlation was found between the expression of type IV collagenase and VEGF (P = 0.0061). These data suggest a double role for type IV collagenase in the metastatic process of NSCLC: (1) facilitating the invasion of tumor cells by the proteolytic cleavage of the basement membrane and (2) similarly supporting the endothelial cell invasion essential for tumor angiogenesis. Furthermore, our findings sustain the hypothesis that metastatic spread and angiogenesis are associated with a clonal expansion of highly angiogenic and invasive tumor cell clones.

Carcinoma, Non-Small-Cell Lung↗