H. D. Mennel

Formale Pathogenese experimenteller Hirntumoren

SummaryRecent experimental results with resorptive carcinogens, inducing tumors of the nervous system, raise the question, whether similar factors may account as well for man. To answer this question, it seems necessary to consider well proved data of human neurooncology as well as aspects of formal pathogenesis in the field of experimentally induced neoplasms.In the experimental production of nervous tumors with resorptive carcinogens, some characteristics are interesting:1.The prominent malignancy of the resulting tumors. This fact can be explained by taking the peripheral neurinomas as an example of the experimental tumors, which correspond almost exclusively to human “malignant neurinomas” or “neurosarcomas”.2.Moreover “multicentric” and “mixed” tumors are regulary found. Pure gliomas in rats only grow in the early stages; later on and particularly in the large pleomorphic brain tumors an admixture of other cell types is met, occasionally with a net separation of center and periphery.3.In the experiments more frequently also very rare blastomas of human pathology can be observed. For instance in certain experimental models some tumors are quite comparable with the medulloepitheliomas or (esthesio-) neuroepitheliomas in man.4.The species of the animals used in the experiments is of considerable influence regarding the kind of the resulting tumors. The knowledge of spontaneous tumors in animals is important in order to evaluate the real oncogenic effect of some of the applied substances. Pituitary adenomas, for instance, which occur in rats spontaneously or after treatment with estrogens are also seen in experiments with resorptive carcinogens, but they may be probably “spontaneous” tumors.5.For the pronounced malignancy and the multiplicity of tumor growth the grade of the carcinogenic stimulus may be responsible. Pathogenetic considerations explaining the mixed nature of the resulting neoplasms are discussed. The influence of species on the kind and localisation of the resulting tumors might be amongst others due to anatomical factors, which are, however, still unknown. In addition to these special features of formal pathogenesis of experimentally induced brain tumors, statistical data of spontaneous tumor growth in man-as age-, sex-, topic distribution and the spectrum of the occuring tumors have to be taken into account.

Experimentally induced malignant neurinomas as transplantable tumors. Morphology andin vitro behaviour

SummaryMalignant neurinomas, induced by ENU in rats, were transplanted on homologous hosts. One tumor originating from a spinal nerve root was followed through about sixteen serial subtransplantations. The growth characteristics of the grafted tumor, its morphologyin vivo andin vitro after explantation as well as its karyotype were described. Possible conclusions concerning the use of transplanted neurogenic tumors in experimental neurooncology as well as their tissue origin were discussed.

Quantitative aspects of transplantation of experimentally induced tumors of the nervous system

SummaryQuantitative aspects of transplantation have been studied experimentally in ethylnitrosourea-induced nervous system tumors. The number of cells needed for successful transplantation, the biological behaviour-increase of malignancy — of the tumor in relation to the number of cells used during the various passages, and the relationship between number of grafted cells and induction time have been examined. A “critical” number of cells was necessary to ensure a positive result; thereafter, the induction time was directly related to the logarithm of the number of cells implanted.

Zur Morphologie transplacentar erzeugter neurogener Tumoren beim Goldhamster

SummaryPregnant Syrian hamsters were given 30 mg/kg ethylnitrosurea on the 15th day of pregnancy. Among 29 newborn animals, 22 could be grown up, 14 of which developed malignant tumors. Besides tumors of the trigeminal nerve which appeared first, particularly tumors of peripheral nerves were observed. In addition one nephroblastoma and one melanoma of the subcutis were induced. There were no tumors of the brain and spinal cord. The peripheral nervous tumors showed intensive regressive changes. In general, these tumors can be classified within the group of “malignant neurinomas”.

Gross vascularization of experimentally induced transplanted tumors of the central and peripheral nervous system

SummarySubcutaneously and intracerebrally transplanted neurinomas as well as intracerebrally grafted gliomas, both derived from primary tumors with resorptive carcinogens were investigated after injection of micropaque by conventional histologic methods and by postmortem X-ray analysis. Growth pattern and vasculature were similar in subcutaneously and intracerebrally transplanted malignant neurinomas. The most common feature was a parallel arrangement of vessels as shown by microradiography and vessel free zones. In intracerebrally grafted glioma, the growth of tumors was confined to or starting from the ventricular system. Sinusoidal vessels, capillary proliferations and proliferation of vessel wall were found. The outstanding feature was the occurrence of extravascular contrast deposits, thus indicating the vulnerability of tumor vessels and frequency of hemorrhages into these tumors.

Brain tumor chemotherapy using a rat glioma model.

SummaryThe antitumor agent chloroethyl-cyclohexyl-nitrosourea (CCNU) was examined using a rat glioma model. A i.p. administration of three times 40 mg/kg CCNU was highly effective and increased the life-span of tumor-bearing rats from 53 to 86%. A total quantity of CCNU amounting to less than 30 mg/kg was not effective. On the other hand, large dosages exceeding LD10 proved to be toxic.The depression of platelets and white blood cells was mild after a single dosage of 40 mg/kg CCNU which recovered on about the 6th day.In the CCNU-treated animals there was an increase of the extent of necrobiosis. Ballooning of tumor cells with nuclear pyknoses and a lack of mitotic features occurred. Microcystic changes appeared sometimes to be more frequent than in control groups.

Gewebekulturuntersuchungen an experimentell erzeugten, transplantierten malignen Neurinomen

SummaryTwo malignant neurinomas induced with ethylnitrosourea, and of different localization and morphology were transplanted. The first transplants were morphologically very similar to the original tumor. In the explants of these tumors, whether obtained from the original tissue or after trypsination, similar cell types were observed: A bipolar spindle cell and a flat stretched “fibroblast” with a large nucleus. Intermediate forms, particularly a macrophage-like round cell had similarities with the bipolar cells. These results are consistent with earlier findings obtained with the in vitro culture of benign neurinomas. The bipolar spindle cells are considered to originate from Schwann cells.ZusammenfassungZwei mit Äthylnitrosoharnstoff erzeugte maligne Neurinome unterschiedlicher Lokalisation und unterschiedlicher Morphologie wurden transplantiert. Im ersten Transplantat war die Morphologie der Primärgeschwulst noch weitgehend erhalten. Bei der Explantation dieser Geschwülste, sowohl in der Stückchenkultur als auch nach Trypsinierung, wurden in allen Fällen gleichartige Zelltypen beobachtet: Eine bipolare Spindelzelle und ein flach ausgebreiteter, großkerniger „Fibroblast“. Übergangsstufen, darunter eine makrophagenähnliche Rundzelle, besaßen Ähnlichkeit mit der Spindelzelle. Die Übereinstimmung dieser Befunde mit Ergebnissen der in-vitro-Kultur benigner Neurinome wird herausgestellt. Die bipolaren Spindelzellen werden als Schwannsche Zellen interpretiert.

Morfologia dos tumores de hipofise em ratos

Pituitary tumors in rats can be induced by estrogens. They also occur spontaneously in various frequencies depending on strain, sex and age of the animals. They were considered to be hormone-dependent (mammotropic). However, morphologically they were mostly described as chromophobe pitutary adenomas. This does not contradict hormonal activity if one assumes that a degranulation during this activity in tumor cells takes place. METHODS: 81 pituitary adenomas were analysed histologically. They had been observed during experiments with resorptive carcinogens which either produced tumors in the intracranial cavity or were supposed to do so. One tumor was transplanted subcutaneously. Several passages of this tumor were followed up histologically and by electron-microscopy. In addition, these tumors were explanted in vitro. RESULTS: Pituitary adenomas were found in rats which were 623 ± 200 days old; 74 were females, 5 were male. The morphology of rat pituitary tumors was characterized by two cells types: the one consisted of small dark cells that were considered to be stromal elements; the other cells, the true adenoma cells, were epithelial elements in which no specific granulations could be found with the usual methods. Only few tumors had mitoses, infiltrative growth and celular pleomorphism. Tumors were rich in vasculature. Transplanted tumors grew regularly in isogenic rats. The induction time was over 200 days in the first six and about 150 days in the 7 th-10 th passages. Histologically, these tumors were not different from the primary adenomas. In parts, the stromal participation was more pronounced. By electron microscopy highly differentiated cells could be identified. They had many mitochondria, endoplasmic reticulum, vesicles and dispersed hormone granula. Some cells had a very high number of mitochondria, thus resembling oncocytes. The explantation of transplant pituitary adenomas was not successful. Fibroblasts always overgrew the adenoma cells, which had apparently a very low proliferation rate. These tumors probably are hormone-dependent and hormonally active. They can be considered to be spontaneous tumors in rats. However, they exhibited autonomous growth potentialities when transplanted into other hosts. These are benign tumors which have possibility of malignant growth.

Scanning electron microscopy of in vitro grown cells from experimentally induced neurogenic tumors

SummarySerially transplanted neurogenic tumors of experimental origin were explanted in vitro and analyzed by scanning electron microscopy. In explants of intracerebrally transplanted gliomas, small stellate cells with branching processes were observed; in transplanted tumors of the peripheral nervous system, slender bipolar cells as well as fibroblasts emerged. The stereoscopic features were compared with the picture of conventional light microscopy.The findings are consistent with the assumption of the glial derivation of CNS-tumors induced with neurotropic alkylating carcinogens. The peripheral tumors are composed of Schwann-cell like elements and fibroblasts. The significance of the results for the cytogenetic derivation of brain tumors are discussed.