A retrospective survey of endocardial proliferative lesions in rats

Sixty, proliferative, endocardial lesions were diagnosed in 19,304 rats, for an overall incidence of 0.3%. This population consisted of 10,127 Fischer 344, 8,737 Wistar, 200 Sprague-Dawley, and 240 Long Evans rats from chronic/oncogenicity studies reported at Lilly Research Laboratories from 1976 to 1988. Of the 60 proliferative lesions, 44 were classified as endocardial hyperplasia, 15 as endocardial schwannomas, and one as an endocardial sarcoma for prevalence rates of 0.2%, 0.08%, and 0.005%, respectively. Affected rats ranged in age from 42 to 110 weeks. There were no sex or treatment-related differences in the prevalence of the rat endocardial proliferative lesions. A review of endocardial lesions in 18 of 233 Wistar rats treated with carbamate derivatives revealed endocardial hyperplasia in 12 rats, schwannomas in five rats, and a sarcoma in one rat. One of the 12 rats with endocardial hyperplasia also had an intramural schwannoma. Of 200 Wistar rats given N-nitroso-N-methylurea, two had endocardial hyperplasia, and one had an endocardial schwannoma. Morphologic features were similar in either spontaneous or treatment-associated hyperplasia or neoplasia of the rat endocardium. Probable Schwann cell origin of the endocardial proliferative lesions was indicated by positive immunohistochemical staining for S-100 antigen in 10/12 spontaneous and 11/14 carcinogen-associated endocardial hyperplastic lesions. Further, 15/16 spontaneous and 6/7 carcinogen-associated neoplasms were immunoreactive to S-100. No tumor metastasis was recorded in either the spontaneously affected or carcinogen-treated rats.     

Endocardial schwannomas in the Wistar rat

Endocardial neoplasms were observed in 13 Wistar rats, 15-30 months old, from a 30-month inhalation study. Eight of the rats were dissected at 30 months and the other five between 15 and 29 months. Histologically, the lesions in the heart were diagnosed as endocardial schwannomas. Two of the 13 schwannomas were malignant, while the rest were benign. One malignant schwannoma metastasized to the thymus and the other metastasized to the aorta, oesophagus, liver and spleen. Some schwannomas appeared as early lesions limited to the endocardium consisting of round to ovoid cells interspersed with spindle cells, while other schwannomas appeared as advanced lesions consisting of a thin superficial layer of round to ovoid cells and a deeper layer of spindle cells characteristic of endocardial schwannomas. The histological appearance of the metastases was identical to that of the primary tumour. The diagnosis was confirmed by positive immunostaining for S-100 protein. The incidence of endocardial schwannomas in the Wistar rat strain was 1.8%.     

Immunohistochemical characterization of mesothelioma in 6 large felids

Mesothelioma has been reported frequently in large felids. These neoplasms present a diagnostic challenge given their highly variable morphology that mimics carcinomas or sarcomas at different locations. Our goal was to characterize mesotheliomas morphologically and immunohistochemically to determine if a panel of antibodies could be used to more accurately support the diagnosis of these neoplasms in large felids. Mesotheliomas from 6 large felids, including 4 clouded leopards, 1 Bengal tiger, and 1 cheetah, were immunohistochemically labeled for vimentin, E-cadherin, pancytokeratin, Wilms tumor 1 (WT1), MUC-1, and calretinin. The mesotheliomas of the 4 clouded leopards and the tiger were of the epithelial subtype; the mesothelioma from the cheetah was biphasic. All 6 mesotheliomas had strong immunohistochemical labeling for vimentin, E-cadherin, and pancytokeratin. All cases had cytoplasmic labeling for WT1, and 2 also had nuclear labeling. The 3 mesotheliomas with distinct papillary fronds were weakly positive for MUC-1. These and one other epithelial mesothelioma were also positive for calretinin. Our study demonstrates that the morphologic and immunohistochemical phenotypes of mesothelioma that have been identified in humans and domestic species can occur in large felids, and a panel of pancytokeratin, vimentin, WT1, and calretinin can be utilized to support the diagnosis of these neoplasms.     

An ultrastructural study of malignant mesotheliomas in two cows

Malignant mesotheliomas of two Holstein cows were examined by light and electron microscopy. These tumours were derived from peritoneal surfaces and were of biphasic type composed of mesothelial lining cells and submesothelial mesenchymal cells. Ultrastructurally, the neoplastic mesothelial cells were characterized by intermediate filaments, microvilli, desmosomes, tight junctions and basal laminae. The neoplastic submesothelial cells were closely associated with collagen filaments and some cells had several resemblance to the neoplastic mesothelial cells. The ultrastructural features of the mesotheliomas are discussed in comparison with those of adenocarcinomas and fibroblastic neoplasms. In one case of malignant granulosa cell tumour involved the left ovary and its morphology was apparently different from that of the mesothelioma. Multiple primary tumours are uncommon in cattle.     

Mesotheliomas and proliferative lesions of the testicular mesothelium produced in Fischer, Sprague-Dawley and Buffalo rats by methyl(acetoxymethyl)nitrosamine (DMN-OAc).

A single intraperitoneal dose of methyl(acetoxymethyl)nitrosamine (13 mg/kg body weight) given to 78 5-week-old male rats induced 25 mesotheliomas; two mesotheliomas were found in 67 control rats. All mesotheliomas arose from the peritesticular mesothelium and had a typical microscopic appearance of branching papillary fronds with a collagenous core covered by one or many layers of plump tumor cells. Cytoplasm of tumor cells contained material that reacted positively to a colloidal iron stain and was labile to hyaluronidase. In addition to frank mesotheliomas, 16 lesions, which we called atypical mesothelial proliferations, were found. These consisted of a single focus of plump mesothelial cells overlying an area of thick stroma. Often these foci included short, non-branched papillary projections above the surface of adjacent normal mesothelium. Twelve of the 16 lesions occurred in methyl(acetoxymethyl)nitrosamine-treated rats.     

Pathologic features of abdominal and thoracic paragangliomas in F344/N rats

Seventeen paragangliomas were identified in a retrospective review of 200 NTP/NCI carcinogenicity studies in F344/N rats that served either as control or treated animals. Most tumors were grossly visible and located in the retroperitoneum adjacent to the vertebrae and aorta near the kidneys. Three microscopically detected paragangliomas were found at the base of the heart. Microscopically, neoplastic cells were in nests separated by reticulin fibers and capillaries. Argyrophil granules were in the cytoplasm of the retroperitoneal and mediastinal paravertebral tumors. Dense granules were found in the one tumor examined ultrastructurally. Some tumors had areas of necrosis and tumor emboli were present in the lumen of the abdominal aorta and vena cava adjacent to the tumor with metastases present in pulmonary vessels. The incidence of retroperitoneal neoplasms was 3 times more frequent in male than in female F344/N rats.     

Potential role of Anitschkow cells in cardiovascular disease in human and veterinary medicine: A review of the literature

Anitschkow cells (AC) are a peculiar type of stromal cells observed in myocardium, cardiac valves and coronary vessels wall whose origin, characterization and role remain controversial. In human heart, they represent a histological hallmark of Aschoff nodules in rheumatic fever, but they have also been observed in other myocardial pathologies. Firstly, they have been considered a myocyte‐derived cells, but light microscopy, immunohistochemical and ultrastructural studies pointed out that a macrophagic/histiocytic origin cannot be excluded. Many authors also reported extracardiac AC or an Anitschkow nuclear pattern, thus suggesting that these cells may represent a chromatin pattern rather than a specific cell type. In veterinary medicine, AC were described in myocarditis, myocardial necrosis, degenerative and inflammatory endocardial diseases of several species. Recently, AC have been observed in intramural coronary arteries of different animals (including cattle and fish) affected by arteriosclerotic processes. Stress related to the intensive livestock farming could represent a mechanotransduction promoting factor of arteriosclerotic changes allowing the development of Anitschkow chromatin pattern. Further studies both in human and veterinary medicine are needed to confirm the origin and role of these peculiar cells.     

Malignant Lymphoma with Severe Infiltrative Growth into Skeletal Muscles in WBN/Kob Rats

Although spontaneously occurring neoplasms have been reported repeatedly in F344, SD and Wistar rats, which are commonly used strains for routine toxicologic and carcinogenicity studies, there are only a few reports of malignant lymphoma or lymphatic leukemia except for large granular lymphocytic leukemia (LGL) in F344 rats. Malignant lymphoma (lymphosarcoma) is thought to be uncommon in F344 rats. The authors encountered malignant lymphomas of the non-LGL leukemia type with characteristic pathologic features in WBN/Kob rats. The mean age at onset of the disease in all 13 affected rats (8 males and 5 females) was about 60 weeks. Common and characteristic clinical signs were abnormal gait with hind limb paralysis. Macroscopically, the enlargement of the lymph nodes, spleen and liver was slight to moderate. Scattered multiple white-to-gray nodules encompassed the aorta and assumed a bead-like appearance near the thoracic and lumbar vertebrae. Histopathologically, neoplastic proliferative changes were predominant in the bone marrow tissue of the entire body, and many tumor cells infiltrated the spleen and several lymph nodes. The most striking histological features were constant and severe infiltration of tumor cells in the adipose tissue and skeletal muscle adjacent the thoracic and lumber vertebrae. Immunohistochemically, all tumor cells were positive for B-cell markers (PAX-5, CD79a and CD45) and negative for CD3. From the results of immunohistochemistry and morphological examination, these tumors were diagnosed as malignant B-cell lymphomas.     

Malignant mesothelioma in urban dogs

Clinical and postmortem materials from six dogs with a diagnosis of malignant mesothelioma were studied retrospectively. The dogs were urban pets with clinical signs of malignant effusions. Two mesotheliomas were pleural, one pericardial, and one peritoneal. Both pleura and pericardium were involved in one dog, and the pleura and peritoneum in another. On gross examination at necropsy, diffuse granular or velvety plaques covering mesothelial surfaces were found in all dogs; firm discrete pleural nodules also were present in two dogs. Neither distant metastases nor areas of deep lung invasion were found. The tumors varied histologically, but the most common type was epithelial with a papillary pattern. Ultrastructurally, the neoplastic cells had prominent surface microvilli, numerous desmosomes, and tonofilaments. Lung tissue from these dogs and from control dogs was evaluated for the presence of ferruginous bodies. Asbestos bodies were found in three of five dogs with mesotheliomas but rarely were found in control dogs. As a group, the mesothelioma cases had significantly more asbestos bodies and total ferruginous bodies than controls. The clinical and morphologic appearance of canine mesothelioma is similar to human mesothelioma and also may be associated with exposure to airborne fibers.     

Immunocytochemical differentiation of canine mesenchymal tumors in cytologic imprint preparations

BACKGROUND: Immunocytochemical techniques are a potentially valuable diagnostic tool to support cytologic diagnosis in dogs. However, detailed studies of staining patterns and intensity in cytologic specimens of mesenchymal tumor types are lacking. OBJECTIVE: The aim of this study was to evaluate commercially available antibodies against human proteins for use in the characterization of canine tumors of mesenchymal origin in cytologic samples. METHODS: Immunocytochemical staining was performed on air-dried imprint specimens of biopsies obtained from 103 mesenchymal neoplasms and 14 metastatic lesions from 98 dogs. All specimens were stained with anti-cytokeratin AE1/AE3 and vimentin. Based on the histologic diagnosis, tumors of muscle, endothelial, histiocytic, and melanocytic origin also were stained with cell-specific antibodies. Staining intensity was subjectively graded and the percentage of positive tumor cells was estimated. RESULTS: All mesenchymal tumors and metastases, with the exception of mesotheliomas, were vimentin-positive and cytokeratin-negative; mesotheliomas (n=6) were positive for both vimentin and cytokeratin. Tumors of muscle (n=5), endothelial (n=15), and histiocytic (n=18) origin stained moderately to strongly positive in a majority of tumor cells with desmin, von Willebrand factor, and lysozyme, respectively. Malignant melanomas (n=15) had variable staining and a variable percentage of positive cells with Melan-A and S100. CONCLUSIONS: Our results indicate that immunocytochemical staining of canine cytologic specimens is a reliable and sensitive technique that may be of benefit for the differentiation of poorly differentiated mesenchymal tumors and metastases. Additional study is needed to assess the specificity of immunocytochemical stains in mesenchymal tumors.     

Canine cardiac mesothelioma with granular cell morphology

Cardiac mesothelioma with granular cell features was diagnosed in a 10-year-old Golden Retriever presenting with pericardial and abdominal effusions. The diagnosis was based on gross, morphologic, and immunohistochemical features. The immunohistochemical profile of the neoplasm was pancytokeratin positive, vimentin positive, and S-100 negative; most gross and morphologic features were consistent with both mesothelioma and granular cell tumor. To the authors' knowledge, the prognosis for either primary cardiac mesothelioma or granular cell tumor in the dog is unknown. At 4 months after thoracotomy, pericardectomy, and mass excision, this dog was alive and without clinical evidence of pericardial or abdominal effusions. We describe a granular morphologic variant of cardiac mesothelioma in a dog.     

A survey on neoplasia in domestic species over a 40-year period from 1935 to 1974 in the Republic of South Africa. II. Tumours occurring in sheep

A survey was carried out on all ovine neoplasms recorded in the registration files of the Section of Pathology of the Veterinary Research Institute at Onderstepoort over a 40-year period from 1935 to 1974. The neoplasms were divided and tabulated into 8 groups according to body systems or tissue types. Out of a total of 673 neoplasms, 436 (64,8%) were cases of jaagsiekte (pulmonary adenomatosis). Of the remaining 237 neoplasms, 41,3% involved the skin. Eighty per cent of the cutaneous neoplasms were squamous cell carcinomas which varied from well-differentiated to anaplastic. The majority occurred on the head, in particular on the ears, frontal region and on the eyelids or nictitating membrane. Several factors have been suggested to explain the high incidence of squamous cell carcinomas on the head. Lymphosarcomas were the 3rd most commonly encountered tumours, whilst a significant number of hepatocellular carcinomas also occurred. A variety of tumours of connective tissue origin were recorded, the most common of which arose from fibrous tissue and cartilage.     

Spontaneous eosinophilic granulated round cell tumors in rats

Morphologic and histochemical characteristics were noted for three spontaneous tumors with eosinophilic cytoplasmic granules that occurred in aged Fischer 344 rats. Macroscopic lesions were widely distributed in the body, mainly involving the intra-abdominal adipose tissue, pancreas, and mesenterium. These lesions were generally hard swellings with nodular and sclerosing areas. Bloody ascites was a concomitant finding. Histologically, the tumor cells were round, from 9 to 30 microm in diameter with one or two round to oval nuclei, and characterized by eosinophilic granules (0.5-2.0 microm) that stained definitely to weakly positive with the periodic acid-Schiff reaction and demonstrated no metachromasia with toluidine blue stain. Furthermore, the granules were characterized by a positive reaction with lectin histochemistry for concanavalin A (Con A), wheat germ agglutinin (WGA), phaseolus vulgaris agglutinin (PHA-E4), lens culinaris agglutinin (LCA), and recinus communis agglutinin (RCA-I) in all tumors and for ulex europaeus agglutinin (UEA-I), peanut agglutinin (PNA), and soybean agglutinin (SBA) in one tumor. Positive reactions for anti-rat mast cell protease II and CD8 were not demonstrated immunohistochemically. Abundant glycogen was noted in the large tumor cells from one rat. With electron microscopy, the cytoplasmic granules were identified as electron-dense homogenous bodies bounded by a single unit membrane. These characteristics are similar to those of granulated metrial gland cells, but further study is needed to clarify the cell of origin for these tumors.     

Histological comparison of malignant epithelioid mesothelioma in young and adult cattle

The histology and immunohistochemistry of pleomorphic and conventional epithelioid mesotheliomas were examined. The former was detected in two young calves aged 2 and 4 months and was characterized by pleomorphic and atypical cells with decreased expression of cytokeratin 7 (CK7). In contrast, the latter was found in a 31-month-old heifer, consisting of tumor cells uniform in size and shape with CK7 expression in nearly all cells. Production of collagen by tumor cells was demonstrated in both histological types, and was considered to be characteristic of bovine epithelioid mesothelioma. Pleomorphic mesothelioma is far more pleomorphic and mitotically active than conventional mesothelioma, and its normal counterpart may be immature mesothelial cells with high proliferation potential, which exist in fetal life and early calfhood.     

Primary renal neoplasms of the dog.

Of 48 canine primary renal neoplasms found in the files of the Armed Forces Institute of Pathology, 36 were of tubular cell origin (five adenomas and 31 carcinomas), six of transitional cell origin (two papillomas and four carcinomas), two were nephroblastomas and four were nonepithelial. With the exception of nephroblastomas, renal neoplasms occurred in dogs older than 5 years and were most common in males. No breed predilection was apparent. Eight of the neoplasms were classified by histologic criteria as benign and 40 as malignant. Seventeen of the malignant neoplasms had metastasized. The neoplasms of tubular cell origin contained solid, tubular and papillary patterns, often mixed within the same tumor.     

Occurrence of Spontaneous Tumors in the Central Nervous System (CNS) of F344 and SD Rats

In order to accurately assess the carcinogenicity of chemicals with regard to rare tumors such as rat CNS tumors, sufficient information about spontaneous tumors are very important. This paper presents the data on the type, incidence and detected age of CNS tumors in F344/DuCrlCrlj (a total of 1363 males and 1363 females) and Crl:CD(SD) rats (a total of 1650 males and 1705 females) collected from in-house background data-collection studies and control groups of carcinogenicity studies at our laboratory, together with those previously reported in F344 and SD rats. The present data on F344/DuCrlCrlj rats (F344 rats) and Crl:CD(SD) rats (SD rats) clarified the following. (1) The incidences of all CNS tumors observed in F344 rats were less than 1%. (2) The incidences of malignant astrocytoma and granular cell tumor were higher in male SD rats than in female SD rats. (3) The incidences of astrocytoma and granular cell tumor were higher in SD rats than in F344 rats. (4) Among astrocytoma, oligodendroglioma and granular cell tumor, oligodendroglioma was detected at the youngest age, followed by astrocytoma, and ultimately, granular cell tumor developed in both strains. The incidences observed in our study were almost consistent with those previously reported in F344 and SD rats.     

Fordyce's granules of the incisor and molar gingiva in F344 rats

Fordyce's granules were observed in the gingiva of the upper incisor and molar teeth in F344 rats. The data were based on 734 males and 722 females that were used as control and treated animals in 26-week, 65-week, and 2-year studies by the National Toxicology Program. The incidence of Fordyce's granules was markedly different when comparing sex, age, and site of the lesion. Fordyce's granules were very common in the midsagittal gingiva of the upper incisor in males and increased in incidence with age (34.2, 50, and 56.3% in 26-week, 65-week, and 2-year studies, respectively). The granules of the incisor gingiva were rare in females (0,0, and 2.8% in 26-week, 65-week, and 2-year studies, respectively). Fordyce's granules of the molar gingiva were very rare in both sexes and were found only in 9/734 (1.2%) males and in 3/722 (0.4%) females. Only three unilateral granules of the molar were grossly recognized as focal swelling of the gingiva or a white nodule with a huge cyst in the third upper molar. Histologically, Fordyce's granules were arranged as a collection of sebaceous glands unassociated with hair follicles. In addition, the granules of the molar gingiva were associated with cystically dilated ducts filled with sebum. Ultrastructurally, the sebaceous cells were characterized by varying numbers of cytoplasmic lipid droplets and occasional desmosome and hemidesmosome formation. Fordyce's granules previously reported in rats of other strains were also reviewed and compared with those in F344 rats in regard to incidence, location, and age.     

Malignant pleural mesothelioma in a woodchuck (Marmota monax)

A spontaneous pleural mesothelioma was observed in a 4-year-old female woodchuck (Marmota monax). At necropsy, multifocal, tan to white, firm discrete nodules, 2 to 40 mm in diameter, were scattered over the ventral parts of the lungs and their corresponding parts of the diaphragm and the thoracic wall. Histopathologically, the tumor cells were large, cuboidal-shaped and variable size, and were weakly positive with PAS and Alcian blue. Immunohistochemically, neoplastic cells were positive for both vimentin and cytokeratin, indicating mesothelial origin. This report represents, as far as we know, the first reported case of a spontaneous mesothelioma in woodchucks.     

Availability of a Microglia and Macrophage Marker,Iba-1, for Differential Diagnosis of Spontaneous Malignant Reticuloses from Astrocytomas in Rats

In rats, it is sometimes difficult to distinguish malignant reticuloses from astrocytomas in routine histopathological assessment. In the present study, four spontaneous brain neoplasms developing in the cerebrum of one Wistar Hannover rat and three Sprague-Dawley rats were immunohistochemically examined using microglia and macrophage markers. Histopathologically, these neoplasms were localized mainly in the cerebral cortex, hypothalamus or piriform lobe, and the portions showing solid growth did not show characteristic cellular arrangement but had an indistinct boundary with the surrounding brain parenchyma. Neoplastic cells had oval or pleomorphic small nuclei with abundant eosinophilic cytoplasm. Two cases showed neoplastic cell infiltration into the meninges and perivascular spaces. Silver staining showed lack of reticulin fiber production in the stroma of the neoplasms. Immunohistochemically, the neoplastic cells were strongly positive for Iba-1 and sporadically positive for CD68 in all four cases. On the basis of these results, all the neoplasms examined here could be distinguished from astrocytomas and diagnosed as malignant reticuloses. Thus, immunohistochemical demonstration of microglia/macrophage characters, such as using Iba-1, is considered to be helpful for differential diagnosis of malignant reticuloses from astrocytomas among spontaneously occurring primary brain neoplasms in rats.     

Spontaneous amelanotic melanomas of the uveal tract in F344 rats.

Five intraocular amelanotic melanomas were identified in the National Toxicology Program's database consisting of records from more than 60,000 female and 60,000 male F344 rats, which were used as control and treated animals in 2-year carcinogenicity studies. The five spontaneous melanomas were grossly observed as white or yellow, unilateral nodules, which originated in the region of the iris and ciliary body, often also involving the choroid. These amelanotic melanomas were composed predominantly of spindle cells arranged in a whorled pattern often with perivascular orientation. Mitotic figures were common in five tumors. The spindle cells had a positive immunoreactivity for S-100 protein but were negative for desmin. Electron microscopic studies provided clear evidence that these tumors originated from the uveal melanocytes. Ultrastructurally, the spindle cells contained numerous cytoplasmic premelanosomes (stage II melanosomes) that were not associated with melanin. Special histochemical studies showed that the spindle cells had a negative reaction for melanin. Although electron microscopic features are critical in the diagnosis of amelanotic melanomas of the uveal tract, the whorled pattern of spindle cells is a useful histologic criterion in differential diagnosis of this tumor in F344 rats.