H. Gabbert

Tumor dedifferentiation: An important step in tumor invasion

Tumor invasionin vivo was studied by light and electron microscopy as well as by immunofluorescence microscopy. Special regard was paid to the grade of tumor differentiation. Dimethylhydrazine-induced murine colonic carcinomas comprising a differentiated and an undifferentiated tumor type with low and high invasiveness respectively, were used. At the invasion front of both tumor types a striking dissociation of the organized tumor cell complexes into isolated tumor cells was found together with a loss of most of the cytological features of differentiation. It is supposed that this process mobilizes the tumor cells from the main tumor bulk enabling them to invade the host tissue by active locomotion. This view is strongly supported by the demonstration of morphological equivalents of active cell movement such as pseudopodia-like cytoplasmic extrusions, adaptive changes of the cell shape and microfilament bundles. Although the proposed mechanism of tumor invasion is essentially the same in both tumor types, the grade of differentiation is nevertheless critical, as in the undifferentiated carcinomas only subtle dedifferentiation steps (loss of basement membrane and cell junctions) are necessary to acquire an invasive status. This fact may explain the comparatively high invasiveness and poor prognosis of undifferentiated carcinomas.

Differentiation and aging of the rat intestinal mucosa. II. Morphological, enzyme histochemical and disc electrophoretic aspects of the aging of the small intestinal mucosa

At different times of day (08.00, 12.00, 16.00 and 24.00) the small intestinal mucosa of four month (adult) and 30 month (senile) old rats was examined histologically, by scanning electron microscopy, autoradiography, enzyme histochemistry and disc electrophoresis. In senile rats a villous atrophy is found histologically and an irregular architecture is found in scanning electron microscopy. The changes are essentially restricted to the proximal small intestine. The enterocytes of adult and senile rats show an identical enzyme histochemical picture. In the proximal small intestine of adult and senile rats, synchronous statistically significant fluctuations of the activity of alkaline and acid phosphatase were revealed in the disc electropherograms. Likewise statistically significant are the at all times of day low enzyme activities in the intestinal mucosa of senile rats as compared to the findings in adult rats. The fall in activity of alkaline and acid phosphatase in old rats is attributed to the numerical reduction of the enterocytes which is caused by the age atrophy of the intestinal mucosa. These findings are discussed in connection with results of our own studies of proliferation kinetics and those of other authors.

The relation between tumor cell proliferation and vascularization in differentiated and undifferentiated colon carcinomas in the rat

SummaryTumor cell proliferation and tumor vascularization were investigated in differentiated and undifferentiated colon carcinomas of the rat. The following results were found: 1, in both tumor types, vascularization is developed equally well; 2, both in the differentiated and in the undifferentiated carcinomas, the number of proliferating tumor cells decreases with increasing distance from the capillaries; at a distance of about 80 μm, there is no longer any noteworthy tumor cell proliferation; 3, the differentiated and undifferentiated carcinomas differ both in the level of the mitosis index and3H-thymidine labeling index as well as in their local proliferation pattern despite equal vascularization; 4, these differences must be based on factors which are independent of vascularization; they are attributed to proliferation properties which are inherent in the differently differentiated tumor cell populations. It is concluded from this that the actual proliferation behavior of a carcinoma is primarily dependent on the proliferation properties of the tumor cell population.

Sarcoma of the pulmonary artery: Report of two cases and a review of the literature

SummaryPrimary tumours of the pulmonary arteries are rare neoplasms seldom diagnosed during the patients life time. We report on two cases of pulmonary artery sarcomas diagnosed during life time of the respective patients in intra-operative frozen sections by histopathological examination. Case 1 was of a 55-year-old man with a fibrosarcoma originating from the main pulmonary trunk. Case 2 was of a 43-year-old woman with a malignant fibrous histiocytoma originating from the right pulmonary artery. In both patients a radical tumour resection under cardiopulmonary bypass was attempted. Both patients, however, had a local tumour recurrence and died 18 months (patient 1) and 6 months (patient 2) after surgery. A review of pulmonary artery sarcomas is given.

Grades of atypia in tubular and villous adenomas of the human colon. An electron microscopic study.

SummaryOf a total of 544 tubular, villous and tubulo-villous adenomas of the human colon which were investigated by light microscopy, six tubular and six villous adenomas were examined under the electron microscope. It was shown that the two types of adenoma differ in their tissue architecture, but not in their cytological appearance.Different grades of epithelial atypia occur in both types of adenoma. These are designated as grades I to III, corresponding to mild, moderate and severe atypia respectively. Whereas adenoma cells with atypia grade I clearly show a cytological relationship with the crypt epithelia of the normal colonic mucosa under the electron microscope, adenoma cells with atypia grade III have largely lost the differentiation characteristics of the parent cells and there is no longer intracytoplasmic organization. In the cytoplasm of adenoma cells with atypia grade II, glycogen storage is found as a special feature which does not occur in normal colonic epithelium. A similar finding has been described in the course of malignant transformation of the liver and kidney and thus can be regarded as a further indication of the precancerous nature of the adenomas.

The intraclonal and interclonal phenotypic heterogeneity in a rhabdomyosarcoma cell line with abortive imitation of embryonic myogenesis

SummaryThree distinct subpopulations (A, B, C) derived from a dimethylbenzanthracene-induced rat rhabdomyosarcoma were established as permanent cell lines. Although the clonal nature of each of these subpopulations was confirmed by repeated recloning procedures, a striking intraclonal phenotypic heterogeneity was observed. By means of immunofluorescence microscopy and transmission electron microscopy, it could be shown that these subpopulations closely recapitulate stages of embryonic rhabdomyogenesis both in vitro and in vivo, but differ in their particular range of maximum differentiation. Embryonic rhabdomyogenesis is imitated most perfectly by subpopulation C, in which multinuclear myotubes are formed in vitro by fusion of mononuclear cells, and α-sarcomeric actin is expressed in the multinuclear cells and in a few mononuclear cells. After retransplantation in vivo, subpopulation C further proceeds in fine structural differentiation, now exhibiting myofibrils with a sarcomeric organization in the myotube-like giant cells. The cells of subpopulation B do not exceed the stage of mononuclear desmin-positive cells in vitro, but synthesize thin and thick myofilaments after retransplantation in vivo. The cells of subpopulation A recapitulate embryonic rhabdomyogenesis least successfully being confined to the stage of mononuclear desmin-positive cells. Thus, the coexistence of diverse subpopulations and the cellular maturation within these subpopulations together contribute to the phenotypic heterogeneity of rhabdomyosarcomas.

Malignant fibrous histiocytoma of the renal capsule

SummaryWe report about an extremely rare case of malignant fibrous histiocytoma (MFH) of the renal capsule. The tumor is composed of fibroblast-like cells arranged in a storiform pattern and histiocyte-like cells with multinucleated giant cells, both showing no iron reaction. Characteristic of the histiocytic quality of the tumor are numerous PAS-positive intracytoplasmic droplets which can be identified as erythrophagosomes only under the electron microscope. Emphasis is put on the preoperative differential diagnosis of the tumor from renal cell carcinoma as well as on its histogenesis and prognosis.

The mechanism of epithelial shedding after ischemic damage to the small intestinal mucosa

SummaryThe intestinal mucosa of the rat was examined by light and electron microscopy 15, 30, 60 and 120 min after complete ligation of the vessel arcades of the proximal jejunum. The characteristic sign of ischemic damage to the small intestinal mucosa and the reason for epithelial shedding is the appearance of membrane enclosed cytoplasmic blebs which arise at the cell base of the enterocytes and detach the epithelium from the basement membrane. This process begins at the tip of the villi before the enterocytes display signs of irreversible damage and progress to the base of the villi with continuation of the ischemia.

DNA image cytometry: A prognostic tool in rectal cancer?

In 68 patients the DNA content of tumor cells was measured by image cytometry after resection of the rectum because of cancer. In the DNA histogram a differentiation between diploid (n=19), polyploid (n=24), hypotriploid (n=17), and hypertriploid (n=8) tumors was possible. The best relapse-free survival time was found in patients with diploid tumors. The prognosis worsened from polyploid to hypotriploid and was worse in hypertriploid tumors. Testing for a prognostic advantage of diploid over aneuploid tumors without adjustment for additional factors simply by means of the log-rank statistic gave a (one-sided)Pof 0.1013. In a multivariate analysis the degree of differentiation turned out most important. Again, an appropriate test for prognostic relevance of DNA content failed to be significant (P=0.3264).

Terminally differentiated postmitotic tumor cells in a rat rhabdomyosarcoma cell line

SummaryA permanent rat rhabdomyosarcoma cell line (BA-HAN-1C) has been established, the phenotype of which is characterized by the coexistence of undifferentiated mononuclear cells and differentiated multinuclear myotube-like giant cells. The failure of attempts to separate these two cell types by repeated recloning procedures indicates their close histogenetic relationship and suggests that differentiation in this tumor proceeds in a similar manner to that in normal striated muscle where postmitotic myotubes arise from mononuclear myoblasts by fusion. The morphologically undifferentiated mononuclear tumor cells were shown to be actively proliferating and to incorporate thymidine methyl-3H(3H-TdR). The myotubelike giant cells neither incorporated3H-TdR nor underwent mitosis or exhibited any clonogenic potential. After retransplantation into syngenic rats, tumor growth was markedly retarded when the tumor cell inoculum contained a high percentage of myotube-like giant cells. These data show that proliferative activity in this rhabdomyosarcoma cell line is confined to the mononuclear tumor cell compartment, the multinuclear myotube-like giant cells having withdrawn from the cell cycle and represent terminally differentiated postmitotic cells. This cell line should provide a valuable tool for further investigation of coherent aspects of proliferation and differentiation using various differentiation inducers.