[Comments on the contribution by F. Theissig et al. Metastatic malignant vipoma of the pancreas].
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Biomedical subjects
Publications and source records attributed to F Theissig.
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It is supposed that the nucleolar organizer regions (NORs), genes on which ribosomal RNA is coded, may contain information on the structure of the nucleolus and on nucleolar activity which permits discrimination between normal and neoplastic cells and their proliferation activity. In the present study, the histological sections of 144 patients with carcinomas of the oropharynx and hypopharynx were studied in a retrospective approach to determine the absolute NOR counts per 100 nuclei and investigate their influence on the prognosis and extent of lymphogenic formation of metastases. An absolute NOR count of 681 per 100 nuclei was found to give reliable discrimination between stage N0 or N1 carcinomas and stage N2 or N3 disease.
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In primary tumours of 40 patients with invasive ductal carcinomas the significance of nucleolar organizer regions (NORs) for metastatic spread to the axillary lymph nodes and for the prognosis was assessed. Silver-stained tissue sections were investigated by means of semiautomated image analysis. The nucleolar organizer regions of 100 tumour cell nuclei per specimen were measured. The number as well as the area of the NORs were evaluated together with morphometrical and DNA features, histopathological and clinical data. By means of multivariate discriminant analysis, significant differences between tumours of 20 node-negative and 20 node-positive patients could be found. The mean number of NORs was significantly higher in patients with lymph node metastases (p = 0.0059), whereas the mean area was significantly lower in node-positive patients. By using the NOR number as the only parameter both groups were classified with an overall efficiency of 95%. There was also a significant difference between long-term and short-term survivors by considering the mean number of NORs, but the Auer-type, the 2 cDl value, and the DNA-grade of malignancy were of better predictive value. Within the group of node-negative patients the NOR number was most suitable for distinguishing between good and poor prognosis, whereas within the group of node-positive patients once more the DNA parameters played the most decisive role for predicting prognosis. With regard to the small number of patients the results have to be considered as preliminary. Further investigations in a more extensive population are necessary.
Tissue sections were taken from 187 cases of invasive ductal mammary carcinoma (among them 94 cases with lymph node metastases, average follow-up period being 44 months) and, after Feulgen staining, were investigated by automated microscopic image analysis. A comparison was made, with reference to survival periods, between the relevance to prognosis of nuclear image analysis and results obtained from histopathological grading, according to Bloom and Richardson (1957), as well as findings recorded from image analysis of DNA. Histopathological grading was found to be of poor reproducibility (71.1%). While statistically significant differences were found to exist between survival curves of Grades I and III patients, grading proved to be of minor importance to prognostic assessment of the individual case, with the number of G-II cases being relatively high (42.7%). Results of better reproducibility were achievable from the quantitative morphological method of nuclear image analysis. Its forecasting value with regard to good or poor prognosis was clearly higher than that of histopathological grading, and the number of cases with obscure or dubious prognosis was clearly lower (18.9%). DNA ploidy measurement, using DNA histogram types according to Auer (1980), has proved to be another method by which prognostically favourable and unfavourable cases can be distinguished from each other with statistical significance, though its classification quality (70.5%) still was unambiguously below that achievable by nuclear image analysis (79%).
Feulgen-stained tissue sections of 187 invasive ductal carcinomas (94 with lymph node metastases; mean follow-up: 44 months) were studied using computer assisted image cytometry. Based on survival time, the prognostic significance of nuclear image analysis was compared with the results using conventional histopathological grading according to Bloom and Richardson, as well as with image cytometric DNA measurements. The histopathological grading has the disadvantage of poor interobserver reproducibility (71.1%). Despite statistically significant differences between the actuarial survival curves of grade 1 and grade 3 patients, the prognostic significance of the conventional grading method for individual patients seems to be low and the number of grade 2 cases (42.8%) is large. The quantitative morphological method for analyzing nuclear images gives more reproducible results. Compared to histopathological grading, the predictive values for good or poor prognosis are clearly higher and the number of cases with uncertain prognosis is significantly smaller (20.9%). DNA ploidy measurements also make it possible to distinguish statistically significant differences between favorable and unfavorable prognoses with respect to over-all survival time. However, the classification accuracy based on the best single parameter (DNA-histogram type according to Auer) is 70.2% compared with 78.9% for nuclear image analysis.
The ploidy patterns determined for several groups of mammary and gastric carcinomas were subjected to a set of statistical analyses. The DNA distribution patterns were derived from image cytometry measurements of each of at least 150 Feulgen-stained tumour cell nuclei from tissue sections from 84 invasive ductal carcinomas of the breast and from 30 tubular adenocarcinomas of the stomach. Widely used DNA parameters (mean value, standard error of the mean, DNA-malignancy grade, 2c deviation index and the exceeding rate according to Böcking, DNA-histogram types according to Auer, DNA-index according to Atkin) were analysed by univariate and multivariate statistics. The DNA histograms were also analysed multiparametrically. The results showed different prognostic groups of the breast tumours to be distinguishable on single parameters with a reliability of up to 66%. None of these parameters permitted the discrimination of gastric carcinomas. Although the DNA-histogram-analysis increased accuracy by nearly 10%, compared with the classification accuracy of the best single parameters, it is still far from being applicable in clinical diagnostics. The use of further image cytometry parameters will be required for such applications.
A study was conducted to assess the reproducibility and prognostic significance of the histopathological grading by using the criteria of Bloom and Richardson. 166 breast carcinomas of the invasive ductal type (NOS - not otherwise specified) according to the WHO criteria, selected from the biopsy material of the years 1980 to 1988 were investigated. 85 of the patients presented axillary lymph node metastases in the mastectomy specimens. A satisfactory correlation of histopathological grades assessed by three pathologists was found in 72.3% of all cases. Fifteen cases (9%) were over- and 31 cases (18.7%) were underestimated compared with an expert's grade. A disagreement of two grades occurred in one case only. In comparison of grade 1 and grade 3 tumours as well as of grade 2 and grade 3 tumours significant differences in the overall survival could be found. Irrespective of statistically significant differences between the three grades in actuarial survival, the histopathological grading is of rather low value for the prediction of prognosis of individual patients.
The steadily increasing interest in DNA and ploidy determination of malignant tumours led to an increased application of flow image cytometric methods in tumour research and clinical pathology for some years. The investigations are mainly designed to explore the proliferative capacity and deviations in the characteristic DNA-content, finally to obtain clues about the actual malignancy grade and the prognostic outcome of a given malignant tumour therapy. The results of the study on 84 breast and 30 gastric cancers show the principal opportunity to use image cytometric techniques for DNA determination in histological sections. Apart from all disadvantages of these methods compared with flow cytometry, the image cytometry is capable of giving prognostic information with respect to survival as well as to the metastatic potential. Although several significant differences exist between the prognostic subgroups in seven and four DNA parameters, respectively, the case-related decision is not satisfying the clinical demands. Gastric cancers did not show any significant differences on the single-parameter level. Single distinct DNA parameters having the same diagnostic importance in both different tumour types and different prognostic problems could not be found.
The heterogeneity of primary and metastatic tumors was studied on the basis of their nuclear images. Feulgen-stained tissue sections of invasive ductal carcinomas of the breast (84 primaries, 15 lymph node metastases), adenocarcinomas of the stomach (30 primaries) and colorectal adenocarcinomas (30 primaries, 10 lymph node metastases) were investigated by high resolution image analysis. At least 150 tumour cell nuclei as well as 50 diploid reference cells were measured in each case. By means of multivariate statistical analysis significant differences could be found between primary tumors with and without lymph node involvement or distant metastases. In contrast, in a majority of the cases primary tumors and their metastases were largely identical with regard to the nuclear image and the DNA content. Features with high discriminant power for differentiation of metastasising tumors and malignant tumors without metastatic spread were the nuclear area, the number of coarse chromatin particles and other descriptors of the chromatin structure. The DNA content as a useful tool for the prediction of prognosis was of minor importance for the prediction of the metastatic phenotype.
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The importance to prognostication of grading, staging, and image cytometric DNA parameters was investigated in 84 cases of invasive ductal mammary carcinoma. Correlations between tumour size, lymph node condition, and five-year survival were shown to be statistically significant. Similar correlations were found to exist between the grade of histopathological malignancy and various DNA parameters derived from the DNA histogram. However, the relevance of all the above single factors has proved to be of limited value in the individual tumour case. Multivariate analysis of DNA parameters, 80.3 percent in probability, was found to enable the best prognostic prediction of an individual course. These results suggested nuclear DNA content to be an objective marker of biological behaviour of a given tumour.
In primary tumours of 84 patients with invasive ductal carcinomas the prognostic significance of the nuclear image was assessed. Feulgen stained tissue sections were investigated by image cytometry. At least 150 tumour cell nuclei as well as 50 lymphocytes or trout erythrocytes for diploid reference were measured in each specimen. 35 morphological features, including those of the chromatin pattern, were derived from the digitized nuclear images. By means of multivariate discriminant analysis, significant differences could be found between tumours of 41 node-negative and 43 node-positive patients. The differences were sufficiently large to distinguish subgroups with low and high risk of lymph node involvement. Irrespective of lymph node status, 66 patients with an adequate 5 year follow-up were divided into two groups according to their survival time. The classification results revealed a clear relationship between characteristics of the nuclear image and prognosis. By image cytometry it is thus possible to separate both node-positive and node-negative patients into subgroups with increasing risk of recurrence. The results indicate that nuclear image analysis provides prognostic information in addition to established prognostic factors, such as histological grade and tumour stage.
Feulgen-stained tissue sections of 84 invasive ductal carcinomas of the breast (IDC), 30 colorectal adenocarcinomas (ACC), 30 gastric adenocarcinomas (ACG), 10 lymph node metastases of squamous cell carcinomas (SCC) and 11 lymph node metastases of malignant melanomas (MM) were investigated by image cytometry at a spatial resolution of 0.25 micron. At least 150 tumor cell nuclei were measured in each case. By means of multivariate statistical analysis the specificity of the nuclear image for different histological tumor types could be demonstrated in lymph node metastases of SCC and MM. Nuclear image analysis therefore may be a useful tool for pathologists in making the differential diagnosis on metastases of unknown primary tumors. For IDC, ACG and ACC the metastatic phenotype could be identified by nuclear image analysis of the primary tumors. The prognostic significance of the nuclear image has been proved in adenocarcinomas of the stomach. Features of chromatin structure played an important role in both the diagnosis of doubtful histological tumor types and the prediction of lymph node involvement or prognostic outcome.
A fist-size Wilms tumour was recorded from a patient, 29 years of age, seven years after therapeutic irradiation for histologically secured Hodgkin's disease (nodular sclerosis, stage II with involvement of cervical and mediastinal lymph nodes). Nephrectomy was performed on the patient who died of bronchopneumonia on the 30th postoperative day. Autopsy did not reveal any residues of the lymphogranulomatosis or metastases of the nephroblastoma.
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Reported in this paper are twelve cases of allogenic transplantation of half-joints and quarter-joints, following removal of locally delimited tumours. Three transplants were incorporated with functionally satisfactory result to three patients over a period of seven years. Infections and recurrence of tumours were the most frequent causes of failure of transplantations. These results are discussed together with possibilities of future allogenic half-joint transplantations.
The multilocular cystic nephroma is a rare benign renal tumour which has its origin in the metanephrogenic blastema. As to the frequency it occurred in adults and children approximately share and share alike. It is reported on a 54-year-old woman with a right-sided multilocular cystic nephroma, who was operated on under the clinical suspicion of a renal carcinoma.