Pathology of spontaneous malignant fibrous histiocytoma in a Japanese white rabbit

Spontaneous malignant fibrous histiocytoma (MFH) of the chest wall was found in a 10-year-old male Japanese white rabbit. Histologically, the MFH consisted mainly of areas of storiform, pleomorphic and myxoid patterns. Positive reactions for acid phosphatase (Ac-P), non-specific esterase (N-SE) and beta-glucuronidase (beta-GL) were demonstrated in fibroblast-like, histiocyte-like and giant cells. Moreover, a strongly positive fibronectin (FN) reaction was observed mainly in histiocyte-like and giant cells. In electron microscopy, tumor cells were composed morphologically of various types of cells such as fibroblast-like, histiocyte-like, undifferentiated and giant cells. This case was quite similar to those reported in man or other animals.     

Neuroendocrine (ECL cell) differentiation of spontaneous gastric carcinomas of cotton rats (Sigmodon hispidus).

BACKGROUND AND PURPOSE: Female inbred cotton rats develop adenocarcinomas in the oxyntic mucosa. Since a female preponderance is typical for enterochromaffin-like (ECL) cell tumors, we examined such tumors for ECL cells. Gastrin plays a decisive role in ECL cell tumorigenesis, so blood gastrin concentration and gastric mucosal pH were measured. METHODS: The stomachs from six female cotton rats (6 to 8 months old) were studied histologically, and at euthanasia, gastric mucosal pH was determined. Euthanasia was performed on 15 other female cotton rats of similar age for determination of blood gastrin values by radioimmunoassay (RIA) and gastric mucosal pH. Rats were classified macroscopically to have normal or thick oxyntic mucosa, with or without tumor. RESULTS: Among the six cotton rats studied histologically, two 6-month-old rats had normal and two others had thick gastric mucosa, whereas two 8-month-old rats had thick mucosa with tumors. The ECL cells were markedly hyperplastic in all rats with thick mucosa, and ECL cells were found in the neoplastic parenchyma. All cotton rats with normal-appearing gastric mucosa had pH <2.5, whereas 14 rats with thick mucosa had pH >3.1 and hypergastrinemia. CONCLUSIONS: Gastrin may play a major role in ECL cell hyperplasia and, perhaps, in adenocarcinoma genesis.     

Malignant fibrous histiocytoma (MFH). A comparison of MFH in man and animals. A critical review.

This review gives information about localization and types of MFH in man and animals such as mouse, rat, cat, dog, opossum, cattle, horse and birds [e.g. mallard (a wild duck)]. Furthermore, this paper reports about cell culture dealing with MFH. The aim of this publication is to show that MFH originates from a primitive mesenchymal stem cell, fibroblastoid cell and fibroblasts. Histiocytes are, according to the literature in a small amount constituents of MFH and are reactive cells or without any meaning. In our own studies using rats [strain: Chbb: THOM (SPF)] the characteristic storiform or cartwheel pattern of tumour cells were evident. The cells were elongated, rich in endoplasmic reticulum and possessed no or very few lysosomes. The cells were predominantly fibroblasts and fibroblastoid cells. These cells were intermingled with giant cells. In other species mentioned above, the MFH showed very similar histological features. Our own results and findings obtained from the literature support our concept that the MFH represents a primitive phenotype or pleomorphic sarcoma which may differentiate in one or more directions. Histiocytes are not a neoplastic component.     

Analysis of the Distribution of Magnetic Fluid inside Tumors by a Giant Magnetoresistance Probe

Magnetic fluid hyperthermia (MFH) therapy uses the magnetic component of electromagnetic fields in the radiofrequency spectrum to couple energy to magnetic nanoparticles inside tumors. In MFH therapy, magnetic fluid is injected into tumors and an alternating current (AC) magnetic flux is applied to heat the magnetic fluid- filled tumor. If the temperature can be maintained at the therapeutic threshold of 42°C for 30 minutes or more, the tumor cells can be destroyed. Analyzing the distribution of the magnetic fluid injected into tumors prior to the heating step in MFH therapy is an essential criterion for homogenous heating of tumors, since a decision can then be taken on the strength and localization of the applied external AC magnetic flux density needed to destroy the tumor without affecting healthy cells. This paper proposes a methodology for analyzing the distribution of magnetic fluid in a tumor by a specifically designed giant magnetoresistance (GMR) probe prior to MFH heat treatment. Experimental results analyzing the distribution of magnetic fluid suggest that different magnetic fluid weight densities could be estimated inside a single tumor by the GMR probe.     

Bronchial brushing cytology features of primary malignant fibrous histiocytoma of the lung. A case report

BACKGROUND: Malignant fibrous histiocytoma (MFH) of the lung is rare. Early diagnosis is very important because of its poor prognosis. Long-term survivors of pulmonary MFH are patients who had surgical resection. When the patient can undergo surgery after a prompt diagnosis, the prognosis improves more than with other therapy. However, it is not easy to establish the diagnosis of thoracic MFH. In general, the small fragments from bronchial or percutaneous transthoracic fine needle aspiration (FNA) biopsies are inadequate for cytologic or pathologic analysis. Bronchial brushing cytology is greatly superior to FNA cytology because one can obtain a large amount of cells. Therefore, bronchial brushing cytology may play a useful role in diagnosis when endobronchial involvement is found. CASE: A 65-year-old female was admitted with a cough, yellow sputum and exertional dyspnea. A chest roentgenogram showed a 12 x 12-cm mass in the left lung field. Bronchial brushing cytology revealed many fibroblastlike, histiocytelike, bizarre and multinucleated giant cells in a background of necrosis. Atypical mitotic figures were also found. The cytologic findings strongly suggested MFH. Although the pathologic findings from FNA biopsy showed storiform clusters structured by pleomorphic, fibroblastlike cells with bizarre nuclei and mitotic figures, the material was too small to diagnose it definitively. Six months later the patient died. An autopsy confirmed the diagnosis of MFH: the typical storiform clusters were composed of many fibroblastlike and histiocytelike cells that were positive for CD68 (PGM1) antibody. CONCLUSION: Bronchial brushing cytology may be a useful method for early, definitive diagnosis of MFH. The presence of pleomorphic, spindle-shaped fibroblastlike and histiocytelike cells with the clusters showing a storiform pattern may permit the diagnosis of MFH.     

Spontaneous bone marrow granulomas in rats--effect of ovariectomy on granulomas formation

Spontaneous granulomas developed frequently in the bone marrow of Slc: Wistar female rats over 19 weeks of age, whereas none did in JCL: SD and Slc: SD rats of either sex. These granulomas were composed histologically of epithelioid cells and macrophages clustered mostly in the center and lymphocytes and plasma cells located in the periphery, and they contained neither microorganisms nor foreign bodies. Ovariectomy of Slc: Wistar rats at 6 weeks of age resulted in a significant decrease in the incidence and size of bone marrow granulomas at 20 and 24 weeks of age. It is concluded that two factors, the strain of rats and female sex hormone, contribute to the pathogenesis of bone marrow granulomas--the former as a hereditary disposition and the latter as a promoter.     

Carcinoma of the breast with malignant epithelial giant cells. Needle aspiration cytology, immunocytochemistry and electron microscopy in a rare case in a woman under 30.

Needle aspiration cytology, immunocytochemistry and electron microscopic findings are described in a case of rare breast carcinoma with bizarre, malignant giant cells in a young female under age 30. The malignant tumors were found in both breasts; the first one was diagnosed when the patient was 23 years of age and the second one in the contralateral breast four years later. Based on our present findings, and in keeping with a similar case recently described by us as occurring in an elderly female, we thought that the bizarre giant cells in this rare breast carcinoma were of epithelial origin. The differential diagnosis of other conditions that may be associated with giant cells in breast aspirates is discussed.     

Metamorphosed fibroblasts and their relation to the histogenesis of malignant fibrous histiocytoma in experimental murine model

Malignant fibrous histiocytoma (MFH) is a clinicopathologically established entity, but its histogenesis remains to be clarified. We have reported the existence of a specific cell type, the "fibrohistiocytoid (FH) cells", in various chronic inflammatory tissues. The FH cells are the metamorphosed fibroblasts and we have revealed the morphological resemblance between FH cells and MFH cells. In the present study we carried out some experiments to ascertain whether the FH cells have a possibility of neoplastic potential for the development of MFH in mice. A total of 50 female Balb/c mice treated with a chemical carcinogen, 9,10 dimethyl-1,2-benzanthracene (DMBA), were examined histopathologically from 8 to 22 weeks after the initial treatment. It was found that 1) the chemically induced tumors in the mice resembled human pleomorphic/ storiform variant of MFH and cells from the tumor were transplantable subcutaneously in the back of another mouse, 2) the tumors were composed mainly of malignant FH cells, and there were many benign FH cells and fibroblasts in granulation tissues obtained at the initial stage of the experiment, 3) all DNA histograms obtained from MFHs were aneuploid and granulation tissues were diploid, and 4) benign FH cells in the granulation tissue appeared to have higher DNA synthesis activity than typical fibroblasts on the basis of bromodeoxyuridine (BrdU) labeling and cytofluorometric studies. From these findings, we suggest that the FH cells are not only a merely morphologically changed fibroblast, but also a biologically ominous cell which may contribute to develop MFH in mice.     

Comparison of verapamil and felodipine treatment on lipid and glucose metabolism in obese female SHHF/Mcc-facp rats.

Calcium channel blockers, verapamil or felodipine, were given to genetically obese 6 and 11-month-old female SHHF/Mcc-facp (SHHF: Spontaneous Hypertension Heart Failure) rats for 8 weeks to investigate their effects on glucose and lipid metabolism and obesity. Both antihypertensive agents significantly decreased systolic blood pressure. In 11-month-old rats, verapamil treatment significantly decreased body weight after 4 weeks whereas with felodipine it was only significantly reduced after 8 weeks. In 6-month-old rats, verapamil significantly curtailed body weight gain. Subcutaneous fat depots were smaller, and abdominal fat depots were larger in verapamil rats compared to felodipine or control rats. Oral glucose tolerance tests in the 6-month-old verapamil and the 11-month-old felodipine groups showed improved glucose tolerance compared to their respective control groups. After 8 weeks of treatment, fasting plasma glucose levels were lower in 6-month-old verapamil rats compared to felodipine and control rats and were decreased by both verapamil and felodipine treatments as compared to control in 11-month-old rats. During the oral glucose tolerance test in 6-month-old rats, both fasting plasma insulin and the area under the insulin curve were increased in verapamil compared to both control and felodipine groups. When compared to controls, plasma cholesterol was increased by verapamil in both age groups, but was significantly decreased by felodipine after 8 weeks of treatment in the 11-month-old group. Plasma triglycerides increased in all control rats compared to initial levels; however, verapamil and felodipine groups showed lower triglycerides in both age groups. In 6-month-old rats, the percentages of plasma HDL significantly increased in both treatment groups as compared to control. This study shows that verapamil and felodipine depressed body weight gain in the young rats, reduced body weight in the old rats, improved lipid parameters and glucose tolerance, but had the opposite effects on body fat distribution and insulin levels in obese female SHHF rats.     

Urinary kallikrein excretion in normotensive aging female rats

The effect of aging on the intrarenal kallikrein-kinin system activity was investigated in normotensive 3-, 10-, 20-, and 30-month-old female Wistar rats. Urinary kallikrein excretion was measured by three independent assays (immunoreactive concentration, kininogenase, and amidolytic activities) and was found to decrease progressively from 10 to 30 months. In the 30-month-old rats the urinary immunoreactive kallikrein excretion represented 40-44% of the level detected in 3-month-old rats. Active and total kallikrein exhibited the same magnitude of reduction. Furthermore, the active to inactive kallikrein ratio remained unchanged throughout the life period studied. The level of urinary kallikrein inhibitor was studied by measuring the recovery of purified rat urinary kallikrein added in the samples; no change was observed with aging. None of the factors known at present to influence kallikrein excretion could be evoked to explain this age-related decrease. It is therefore suggested that this decrease may reflect a progressive impairment of the intrarenal endocrine function or an alteration in the secretion of the enzyme.     

Activation of vasopressinergic and oxytocinergic neurons during aging in the Wistar rat

The activity of the hypothalamo-neurohypophyseal system (HNS) was determined in male Wistar rats from 3 to 32 months of age. Plasma levels of vasopressin (AVP) and oxytocin (OXT) were measured by means of a radioimmunoassay. In addition, the distribution of the Golgi apparatus marker enzyme thiamine-pyrophosphatase (TPP-ase) was measured as a parameter for neurosecretory activity in the hypothalamic supraoptic and paraventricular nuclei (SON and PVN). Plasma levels of radioimmunoassayable AVP were increased in the 32-month-old animals. Plasma levels of radioimmunoassayable OXT in 32-month-old animals did not differe from the levels found in the youngest group, but were higher than in 11-month-old animals. Neurosecretory activity in the SON was similar in 3- and 32-month-old animals, whereas in the PVN neurosecretory activity was increased in the 32-month-old animals. Urine excretion decreased between 6 and 11 months of age and remained on the same level until 32 months of age. In other words, instead of a loss of HNS function as has been suggested in the literature, an increased neurosecretory activity was observed in aged rats.     

Age-related alterations of mitochondria from muscle tissue

The ultrastructure of mitochondria of cross-striated muscles during aging was studied by electron microscopy. Mitochondrial ultrastructure was analyzed in the flight muscle of D. melanogaster (1- and 36-day-old) and in the cardiomyocytes and skeletal muscle of young and senile Wistar and OXYS rats (3- and 25-month-old). The mitochondria in the flight muscle samples of senile D. melanogaster flies were shown to have several types of peculiar age-related mitochondrial abnormalities corresponding to those described previously. Previously unknown changes were revealed in the ultrastructure of cardiomyocyte mitochondria in senile rats (both Wistar and OXYS). Substantial changes in the ultrastructure of subsarcolemmal mitochondria were found in the fibers of red skeletal muscle of senile OXYS rats. It has been shown that the subsarcolemmal mitochondria of red muscle fibers are a peculiar population of mitochondria with atypical ultrastructure. Initial changes in the ultrastructure of subsarcolemmal mitochondria were revealed even in 3-month-old OXYS rats. At the same time, the skeletal muscle mitochondria of senile Wistar rats maintain their morphological characteristics, and their ultrastructure corresponds to that of skeletal muscle mitochondria in 3-month-old Wistar rats.     

Impaired glucose priming of insulin secretion from perfused pancreas in aged female rats.

Effects of age and glucose levels on insulin secretion and synthesis were studied in the perfused pancreas of young (2-month-old) and older (10-month-old) female Wistar rats. Insulin secretion induced by 16.7 mM glucose showed a triphasic pattern: an early spike and fall (first phase, 0-6 min), followed by a sustained gradual increase (second phase, 7-120 min) and a gradual decreased release thereafter (third phase, 121-360 min) during the perfusion period of 360 min. First and second phase insulin secretion, but not third phase, were lower in older rats than in young rats. Insulin synthesis in old rat pancreas perfused with 16.7 nM glucose for 360 min was much greater than that of young rats. Second phase insulin secretion was restored to comparable levels by 28 mM glucose in older rats. Repeated pulses of 28 mM glucose potentiated subsequent insulin secretion in young rats, but not in older rats. These findings provide further evidence that sensitivity to glucose in pancreatic B cells is altered by aging.     

The effect of chronic calcium treatment on thyroid C cells in ovariectomized rats

The purpose of this study was to investigate the influence of chronic calcium treatment on the structure and function of thyroid C cells in ovariectomzed adult female rats. Eighteen 3-month-old, female Wistar rats were divided into three groups. The first group was used as the sham-operated control, and the other two were surgically ovariectomized (Ovx). One month after gonadectomy, one group of Ovx rats was injected with 28.55 mg Ca-glucoheptonate (Ca)/kg b.w., while the other two groups were chronically treated with vehicle alone (Ovx and sham control). Two months after surgery, the animals were killed. In the thyroid C cells, calcitonin (CT) was localized with the peroxidase-antiperoxidase method. Stereology was used to evaluate morphometric changes in the volume of C cells, their nuclei and relative volume density. The number of C cells per unit area was calculated. Serum CT content was determined by radioimmunoassay. After chronic Ca treatment C cells were numerous with darker cytoplasm than in C cells of sham-operated control animals, but more degranulated than the corresponding cells of Ovx rats. Their volume was significantly decreased by 14% (p < 0.05), while the number was increased by 47% (p < 0.05) in comparison with corresponding controls. Serum CT concentration was decreased by 27% (n.s.) in comparison to sham-operated control. Calcium treatment of Ovx rats led to a 32% increase of serum CT concentration in relation to untreated Ovx animals. These results suggest that chronic Ca treatment of Ovx female rats positively affected CT release from thyroid C cells, without any significant changes in morphometric parameters.     

Effect of isoflavone administration on age-related hepatocyte changes in old ovariectomized femal Wistar rats

Aging seems to be due to the accumulation of oxidative damage in cells and molecules. On the other hand, menopause and ovariectomy induce deleterious effects on different organs and systems that have been shown to be counteracted by estrogens and in a not so evident form also with phytoestrogens. The present study has investigated whether the administration of a commercial soy extract that contains approximately 10% isoflavones was able to modify some parameters related to oxidative stress and inflammation in hepatocytes isolated from old ovariectomized female Wistar rats. Eighteen 22-month-old animals that had been previously ovariectomized at 12 months of age were divided into four groups: ovariectomized control rats, estradiol-treated ovariectomized females and ovariectomized rats treated with isoflavones. Six intact female rats of 2 months of age were used as reference group. Hepatocytes were isolated and cultured, and carbon monoxide (CO) and nitric oxide (NO) release, as well as adenosyl triphosphate (ATP), cyclic guanosyl monophosphate (cGMP), phosphatidylcholine (PC) and lipid peroxide (LPO) content of cells were evaluated. Uterus was also removed and weighed. Hepatocytes isolated from old ovariectomized rats showed a decrease in ATP content as compared to young animals. Age also induced an increase in LPO cell content. NO, CO and cGMP were augmented with age, and PC synthesis showed a dramatic reduction. Treatment with either estradiol or isoflavones were able to improve all the mentioned parameters altered in hepatocytes isolated from old ovariectomized rats, and the magnitude of the improvement was similar for both treatments. Ovariectomy induced a significant reduction in uterine weight, which was significantly counteracted by estradiol treatment but not by isoflavone administration. In conclusion, the administration of a soy extract containing isoflavones seems to prevent oxidative changes in hepatocytes isolated from old ovariectomized female rats, without modifying uterus weight.     

Serum gastrin and gastric enterochromaffin-like cells during estrous cycle, pregnancy and lactation, and in response to estrogen-like agents in rats

Histamine-containing enterochromaffin-like (ECL) cells are numerous in the gastric mucosa. They operate under the control of gastrin. ECL-cell tumors (gastric carcinoids) may arise as a consequence of sustained hypergastrinemia. For reasons unknown, such tumors have a female preponderance both in laboratory animals and humans. The present study consisted of four experiments exploring the possibility that gender-related factors might affect rat ECL cells. 1) A gender difference in terms of serum gastrin concentration and oxyntic mucosal histidine decarboxylase (HDC) activity appeared in Sprague-Dawley but not Wistar rats. Ultrastructural appearance of the ECL cells did not differ between genders. 2) During the different phases of the estrous cycle, the serum gastrin concentration, HDC activity and histamine concentration did not change. 3) During pregnancy, the serum gastrin concentration was suppressed, while it was increased during lactation. The HDC activity and the histamine concentration of the oxyntic mucosa were correlated with the levels of circulating gastrin. 4) Twelve-month treatment with estrogen-like agents, dieldrin and/or toxaphene (alone or in combination) was without any effect on the ECL cells neither in male nor in female rats. In conclusion, the ECL cells are under the control of gastrin, but probably not hormones that involve in the estrous cycle and pregnancy and lactation in rats. Possible gender-related factors behind the female preponderance of ECL-cell tumors remain unknown.     

Correlation between gender and spontaneous C-cell tumors in the thyroid gland of the Wistar rat

In many rat strains, C-cell hyperplasia occurs in an age-dependent manner and is often associated with multifocal C-cell carcinoma. The purpose of this study was to investigate the spectrum of spontaneous, proliferative C-cell disorders by gender in Wistar rats throughout their lifespan. The incidence of C-cell hyperplasia shows a significant increase with age (P<0.001) and is much higher in female rats than in male rats (P<0.05). From 3 to 24 months of life, 27.5% of female rats showed a normal C-cell pattern, 55.0% showed C-cell hyperplasia, and 17.5% showed C-cell tumors; while 57.5% of male rats showed a normal C-cell pattern, 32.5% showed C-cell hyperplasia, and 10% showed C-cell tumors. Although the overall frequency of C-cell neoplasms in females was nearly double that in males, these data are not statistically significant. However, the number of C-cell tumors showed a significant increase with age (P<0.05). Therefore, we can conclude that there were significant differences in the incidence of the total spectrum of C-cell proliferative abnormalities in the thyroid gland of Wistar rats that were both age-dependent and gender-dependent.     

Chronic hypoxia induced ultrastructural changes in the rat adrenal zona glomerulosa

The adrenal cortex plays an important role in adaptation to various forms of stress, including hypoxia. While physiological changes in the aldosterone metabolism during hypoxia have been extensively described, few studies have focused on the morphological changes in the adrenal glands under chronic hypoxia. We studied the ultrastructure of the zona glomerulosa of 6-month-old Wistar rats exposed to chronic normobaric hypoxia. Animals were divided into two groups: control (n=12) and hypoxic (n=12). In this latter group, the animals were kept at 7% O2 concentration after a gradual adaptation (21, 15, 12, 10, 8, 7 vol% O2). The duration of the study was 112 days. In comparison with normoxic rats, body weight and adrenal gland weight of hypoxic animals was significantly reduced by 18.5% (p=0.006) and 14.7% (p=0.001) respectively. The thickness of the zona glomerulosa decreased due to atrophy of cells. The main ultrastructural changes observed were: 1) a decrease in, or complete elimination of, lipid droplet content; 2) a marked increase in lysosome number; and 3) the presence of giant mitochondria. Our findings show that rats fail to adapt to severe chronic hypoxia. The ultrastructural changes in the zona glomerulosa found in the present study could reflect changes in the aldosterone pathway.     

Relationship between immune state and tumor growth rate in rats bearing progressive and non-progressive mammary tumors

 Impaired immune responses occur frequently in cancer patients or in tumor-bearing animals, but the mechanisms of the tumor-induced immune defects remain poorly understood. The aim of the present study was to determine the relevance of the immune system in the control of tumor growth. We have developed a model of progressive and non-progressive mammary tumor, chemically induced in female Wistar rats. In this model we evaluated the development of an immune response after immunization of rats bearing progressive and non-progressive tumors with a non-related antigen, such as sheep red blood cells. We also studied the activation state of peritoneal macrophages from animals bearing tumors by evaluating the production of free radicals. Our findings indicated that the cell-mediated immunity in rats bearing progressive tumors fails to respond to heterologous antigen in vivo, as demonstrated by a negative delayed-type hypersensitivity reaction, and is accompanied by minor nitric oxide production by peritoneal exudate cells as well as a lower capacity for macrophage activation. The study of non-progressive tumor-bearing rats indicated that the cell-mediated immune response was intact and an activated state of macrophages was found in vivo. The results described in this paper should be taken into account when therapies based on cancer vaccines are chosen for the treatment of cancer. Received: 26 February 1998 / 9 April 1998     

Fine needle aspiration and touch imprint cytology of a malignant fibrous histiocytoma of the spermatic cord. Case report

BACKGROUND: No cytologic reports on spermatic cord sarcomas have been published. CASE: A 64-year-old man presented with a slowly growing, painless, left spermatic cord enlargement. Fine needle aspiration (FNA) obtained < 1 mL of bloody fluid consisting of solitary, mark-edly anaplastic and pleomorphic tumor giant cells occasionally arranged in small fragments. Rare atypical spindle cells could be observed. Some reactive lymphocytes were observed intermingled with tumor cells. Immunohistochemistry displayed vimentin reactivity and negativity for keratins and leukocytic common antigen. The specimen removed showed a well-circumscribed, 30-mm, yellowish solid tumor. Touch imprints displayed pleomorphic tumor cells showing intense anisonucleosis; a moderate amount of clear, sometimes microvacuolated cytoplasm; and tissue fragments with a storiform pattern. Histologic examination revealed microscopic and immunohistochemical features of malignant fibrous histiocytoma (MFH) arising in soft tissues of the spermatic cord. CONCLUSION: FNA of a spermatic cord lesion may reveal a pleomorphic sarcoma. A pleomorphic appearance together with some spindle elements and compatible immunocytochemistry could help diagnose spermatic cord MFH. This is one of the few reports dealing with FNA cytology of paratesticular tumors and the first report, to the best of our knowledge, showing the cytologic characteristics of a case of spermatic cord MFH.