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Primary cardiac neoplasms are rare in animals. Hemangiosarcoma is the most common primary cardiac tumour in the dog, but has not been reported in the cat. We describe the clinical signs, the gross examination, and the morphological and immunohistochemical features of a haemangiosarcoma in the right atrium of a 13-year-old domestic shorthair cat. In addition, a distant metastasis was found in the liver.
The PIK3CA gene, coding for the catalytic subunit p110alpha of class IA phosphatidylinositol 3-kinases (PI3Ks), is frequently mutated in human cancer. Mutated p110alpha proteins show a gain of enzymatic function in vitro and are oncogenic in cell culture. Here, we show that three prevalent mutants of p110alpha, E542K, E545K, and H1047R, are oncogenic in vivo. They induce tumors in the chorioallantoic membrane of the chicken embryo and cause hemangiosarcomas in the animal. These tumors are marked by increased angiogenesis and an activation of the Akt pathway. The target of rapamycin inhibitor RAD001 blocks tumor growth induced by the H1047R p110alpha mutant. The in vivo oncogenicity of PIK3CA mutants in an avian species strongly suggests a critical role for these mutated proteins in human malignancies.
The serine-threonine kinase Akt is a downstream target of phosphoinositide 3-kinase (PI 3-kinase); it is activated by the phosphoinositide 3-phosphate-dependent kinases PDK1 and PDK2. Certain mutated forms of Akt induce oncogenic transformation in chicken embryo fibroblast cultures and hemangiosarcomas in young chickens. This ability to transform cells depends on localization of Akt at the plasma membrane and on the kinase activity of Akt. A transdominant negative form of Akt interferes with oncogenic transformation induced by the p3k oncogene, which codes for an activated form of PI 3-kinase. Akt is therefore an essential mediator of p3k-induced oncogenicity.
To evaluate the susceptibility of rasH2 mice to N-bis(2-hydroxypropyl)nitrosamine (DHPN), a potent carcinogen targeting the lung, liver, thyroid, and kidney, male, 6-week old, rasH2 mice and wild-type littermates (non-Tg mice) were given DHPN in drinking water at 0, 20 or 200 ppm, and 0 or 200 ppm, respectively, for 26 weeks. The experiment using rasH2 mice given 200 ppm DHPN and non-Tg mice given 200 and 0 ppm DHPN was completed at 20 weeks, since mortality in these groups was remarkably increased due to hemangiosarcomas of the liver. Histologically, tumors developed in the lung and liver in both rasH2 and non-Tg mice treated with DHPN. In addition, proliferative lesions were observed in the forestomach, urethra, and excretory duct of salivary glands in rasH2 mice given 200 ppm DHPN. RT-PCR analysis showed no marked difference in expression of mRNAs for the transgene and the endogenous mouse ras gene between the whole lung tissue containing a neoplasm and normal lung tissue. Our results suggest that rasH2 mice are highly susceptible to DHPN, the target organs including the forestomach, salivary gland and urethra, which have not been found to develop tumors in previous long-term carcinogenicity studies of DHPN in rats and mice.
Vascular tumors and malformations can be challenging to diagnose. Although they can resemble one another, their classification into tumors, such as hemangiomas of infancy, and malformations, such as venous or arteriovenous malformations, is based not only on their divergent biological behavior, but also on their pathogenesis. This review examines the molecular pathobiology of the processes involved in the development of these vascular birthmarks as they are currently understood. The terms hemangioma, hemangiosarcoma, and vascular proliferation are often used interchangeably, even though these entities are clinically and biochemically distinct. A more precise classification is necessary to facilitate communication between basic scientists and clinicians. Vasculogenesis, the in situ differentiation of blood vessels, occurs very early in the developing embryo. In vivo and in vitro studies, as well as knockout models, seem to indicate that this mechanism is unlikely to be involved in the development of either vascular malformations or hemangiomas of infancy. Recent advances in embryonic angiogenesis, especially explorations of mechanisms of vascular remodeling, have brought new understanding of the pathogenesis of vascular malformations. Vascular remodeling, an integral part of angiogenesis that centers upon the interactions between pericytes and endothelial cells, has been shown to be defective in certain experimental models and in some familial cases of vascular malformation. The occurrences of arteriovenous malformations in territories susceptible to increased remodeling also point towards epigenetic events in the development of vascular malformations.
E mu-pim-1 transgenic mice, which overexpress the pim-1 oncogene in lymphoid tissues, have shown increased susceptibility to induction of T cell lymphomas by N-ethyl-N-nitrosourea, a direct-acting chemical carcinogen (Nature, 340, 61-63, 1989). We sought to further evaluate E mu-pim-1 transgenic mice as a potential test animal for a short-term carcinogenesis bioassay. We chose to test four genotoxic procarcinogens; 2-acetylaminofluorene (2-AAF), N-nitro-sodiethylamine (NDEA), 1,2-dichloroethane (1,2-DCE) and benzene (BEN). These compounds require metabolic activation and, with the exception of benzene, are not mouse lymphomagens. Compounds were administered by gavage daily for 38 (NDEA and 2-AAF) or 40 (BEN and 1,2-DCE) weeks to groups of 25-29 male and female PIM mice at 1 and 3 mg/kg for NDEA, 50 and 100 mg/kg for BEN, 25-100 mg/kg for 2-AAF and 100-300 mg/kg for 1,2-DCE. Small but statistically significant increases in the incidence of malignant lymphoma were seen for three of the four carcinogens tested; in high dose males treated with 2-AAF, high and low dose females treated with NDEA and high dose females treated with 1,2-DCE. Results for BEN, the only mouse lymphomagen tested, did not show a statistically significant increase in the incidence of malignant lymphomas in transgenic mice within the 40 week duration of the study. NDEA also produced a high incidence (> 70%) of hepatic hemangiosarcomas in both sexes at the low and high dose levels. These results demonstrate that over-expression of the pim-1 oncogene in lymphoid tissue can confer susceptibility of this tissue to chemical carcinogenesis by genotoxic procarcinogens. However, whereas potent genotoxic carcinogens produced only small increases in the incidence of lymphoma and since BEN, a mouse lymphomagen, was negative, PIM transgenic mice may lack sufficient sensitivity to established carcinogens to justify their routine use in a short-term carcinogenesis screening assay.
Female R rats mated with an R male and inoculated in utero with polyoma virus after "fetectomy" developed tumors. These tumors originated in the uterus and were of fetal origin (visceral yolk sac). Histologically, they were hemangiomas or hemangiosarcomas. The latter were transplantable and grew in tissue culture. Infectious polyoma virus could not be isolated from the tumor cells kept as transplantable lines or cultured in vitro. However, the tumor cells were positive for the polyoma-specific surface antigen, polyoma tumor-specific transplantation antigen(s), and polyoma nuclear T antigen.
Carcinogenic potential of the thiazolidinedione antidiabetic troglitazone was assessed in 104-week studies in mice and rats. Mice were given 50, 400, or 800 mg/kg, male rats 100, 400, or 800 mg/kg, and female rats 25, 50, or 200 mg/kg. Vehicle and placebo controls were included. Survival was significantly decreased in both sexes of both species at high doses, but was adequate for valid evaluation of carcinogenicity. Hypertrophy and hyperplasia of brown adipose tissue was observed in both species at all doses, and fatty change and hypocellularity of bone marrow was noted in mice at all doses and in female rats at 50 and 200 mg/kg. Hepatocellular vacuolation was observed in mice at 400 and 800 mg/kg, and centrilobular hepatocellular hypertrophy occurred in rats at > or = 200 mg/kg. Ventricular dilatation, myocardial fibrosis, and atrial myocyte karyomegaly in male rats at 400 and 800 mg/kg and female rats at all doses were morphologically similar to spontaneous lesions, but incidence and severity were increased compared with controls. In mice, the incidence of hemangiosarcoma was increased in females at 400 mg/kg and in both sexes at 800 mg/kg. The incidence of hepatocellular carcinoma was increased in female mice at 800 mg/kg. Troglitazone exposure [AUC((0-24))] at the lowest dose associated with increased tumor incidence in mice was 16 times human therapeutic exposure at 400 mg daily. No tumors of any type were increased in rats at exposures up to 47 times therapeutic exposure.
The role of hepatic transplantation in patients with nonresectable liver or bile duct cancer remains a controversial issue. An analysis of 95 consecutive cases was undertaken to evaluate retrospectively the pathological tumor stage--in accordance with the TNM system--and outcome after transplantation. Included were patients with the following diagnoses: hepatocellular carcinoma (n = 52), cholangiocellular carcinoma (n = 10), hepatoblastoma (n = 2), hemangiosarcoma (n = 2), bile duct carcinoma (n = 20), and liver metastases from different primary tumors (n = 9). The overall actuarial survival rate at 5 years was 20.4%. Median survival improved significantly within the last 4 years as compared to the preceding era (18.06 vs. 4.0 months). Currently 27 patients are alive, with the longest follow-up more than 12 years. The incidences of residual or recurrent tumor were 27 and 28, respectively. Particularly in patients who underwent transplantation for hepatocellular or bile duct carcinoma without extra-hepatic tumor spread, the results were significantly better; median survival time achieved for these two groups were 120 (p less than 0.01) and 35 months (p less than 0.05). Prolonged survival without tumor recurrence was not seen in patients with cholangiocellular carcinoma or liver metastases. These results demonstrate clearly that liver transplantation for hepatobiliary malignancy is still justified on the premises of careful patient selection by adequate tumor staging.
Twenty-one cases in which sarcomas metastasized to the ovaries are reported. The patients ranged from 18 to 79 (average 42) years of age; only five of them were over 50 years old. Eleven tumors were primary in the uterus and 10 outside the genital tract. Three uterine tumors were leiomyosarcomas, and eight, endometrial stromal sarcomas. The extragenital primary tumors were leiomyosarcoma of the stomach (1) and small intestine (2), retrovesical leiomyosarcoma (1), fibrosarcoma of the anterior abdominal wall (1), sarcoma of the mesentery of smooth muscle or neural type (1), hemangiosarcoma probably primary in the heart (1), osteosarcoma of the maxilla (1), chondrosarcoma of the rib (1), and Ewing's sarcoma of the pubic bone (1). The ovarian tumors, most of which were large, were discovered at the same time as the primary tumors in 11 cases; in seven cases, the ovarian tumor was discovered 7 months to 9 years after diagnosis of the primary tumor. In three cases, the ovarian tumors were discovered 4, 7, and 10 months before detection of the primary neoplasm. Two of these tumors were endometrial stromal sarcomas, and one, an epithelioid leiomyosarcoma of the stomach. Eleven ovarian metastases were bilateral. On microscopic examination, the greatest difficulty in pathologic interpretation was posed by the metastatic endometrial stromal sarcomas because of their simulation of sex cord-stromal tumors. Features helpful in their distinction from these tumors included the frequent presence of extra-ovarian disease, bilaterality, and a characteristic content of small arteries resembling the spiral arteries of the late secretory endometrium. The other tumor that caused major diagnostic difficulty was the metastatic epithelioid leiomyosarcoma from the stomach, which had a pattern that initially suggested the solid-tubular pattern of a Sertoli cell tumor.
Cutaneous angiosarcoma is a relatively rare but devastating malignant vascular tumor. It has a high incidence of recurrence following conventional therapeutic modalities applied either singly or in combination. The increased vascularity of cutaneous angiosarcomas, facilitating selective uptake and retention of a photosensitizing agent, such as hematoporphyrin derivative (HPD), suggests that these tumors would respond well to photoradiation therapy. To study the feasibility of this treatment modality, transplantable hemangiosarcomas were implanted in B6C3F1 female mice. Within 2.5 to 3.5 hours after intraperitoneal administration of HPD, fluorescence was recorded in the tumor as compared with surrounding normal skin. When these photosensitized tumors were exposed to 70 J/cm2 of laser energy from an argon-pumped dye laser at 630 nm, the tumors showed marked necrosis within 24 hours. In another series, the tumors were initially photosensitized with HPD for 3 hours and then treated with laser energy ranging from 0 to 96 J/cm2. A dual labeling procedure demonstrated a dose-related decrease in DNA synthesis rate in tumors that were exposed to 0 to 30 J/cm2 at 24 hours after treatment. Furthermore, tumor tissue exposed to laser energy in excess of 30 J/cm2 showed no significant cellular DNA synthesis. These data, supported by histologic evidence of tissue destruction, suggest that photoradiation therapy has a great potential as a therapeutic modality for cutaneous angiosarcomas.
The contrast medium Thorotrast, an agent well known to be carcinogenic, was injected into 400 congeneic Syrian hamsters. The resulting incidence of malignant hepatic tumors such as cholangiocarcinoma, hepatocellular carcinoma and hemangiosarcoma, was significantly higher in the male experimental group than in the control group, and the 50% survival period in the male group was shortened by about 100 days (P < 0.01). However administration of the antitumor drug PSK (Polysaccharide Kureha), a protein bound-polysaccharide extracted from basidiomycete fungi, prevented this carcinogenic effect. The incidence of malignant hepatic tumors in the experimental group was 22.5% compared with 2.8% in the control group (P < 0.01) and 10.5% in the PSK-treated group (P < 0.01). PSK also increased the 50% survival period by 61 days (P < 0.01).
We report a rare case of thoracic vertebral hemangioma which developed into angiosarcoma during the course of repetitive operations and irradiation. A 44 year old female was operated on for hemangioma of the first thoracic vertebra. The diagnosis of hemangioma was confirmed histopathologically with the specimen from the first operation. The tumor developed multiple lesions later in the clinical course after the first operation, these lesions were removed in four consecutive operations and each histological diagnosis was that of hemangioma. Throughout the period of these operations, the patient was treated with steroid, and with radiotherapy simultaneously. The patient underwent the fifth operation for the recurrence of the tumor on 26 March 1990, and the histopathological diagnosis was not hemangioma but hemangiosarcoma which was considered a malignant transformation. The tumor cells immunohistochemically revealed positive staining with UEA-I, Factor-VIII, as the tumor immunohistochemically showed a vascular endothelioid nature.
Results from transabdominal fine-needle aspiration of the spleen in 28 dogs and 5 cats are reported. Splenomegaly was present in 79% of these patients, and splenic masses were present in 15%. Extramedullary hematopoiesis, the most common cytologic diagnosis, was found in 24% of the patients and was associated with a variety of diseases including immune hemolytic anemia, hemangiosarcoma, and bone marrow hypoplasia. Hematopoietic neoplasms including lymphosarcoma, plasmacytoma, myelogenous leukemia, and systemic mastocytosis were diagnosed in 24% of the patients. Other diagnoses included malignant neoplasia of undetermined cell type and lymphoreticular hyperplasia. Splenic aspirates were considered normal in 18% of the animals. Two (6%) of the aspirates contained liver tissue rather than spleen. Histologic evaluation of splenic tissue was performed in 42.5% of the patients. All cytologic diagnoses correlated well with their final histologic diagnoses. Complications from the aspiration procedure were not observed, even in thrombocytopenic patients.
Splenomegaly confirmed by surgery or necropsy in 100 dogs was diagnosed histologically as benign neoplasia (n = 1), primary splenic malignancy (n = 59), neoplastic metastases (n = 6), and nonneoplastic disease (n = 34). Dogs with known systemic disease, such as lymphoma and mast cell tumor, that caused splenomegaly were not included in the study. Hemangiosarcoma was the most common splenic disease (43 cases). Overall mean age of the dogs was 10.7 years, the most common breed was German Shepherd dog, and 72 of the dogs weighed more than 21 kg. Dogs with anemia, nucleated red blood cells, abnormal red blood cell morphology, or splenic rupture had a significantly greater chance of having splenic neoplasia (P less than 0.002). A multivariable logistic regression analysis found that the presence of anemia and splenic rupture in dogs with splenomegaly was up to 69% accurate in predicting presence of splenic neoplasia. After splenectomy, the median survival time of dogs with splenic neoplasia was 13 weeks. For dogs with nonneoplastic splenomegaly it was at least 36 weeks.
Intramedullary spinal cord metastasis (ISCM) was diagnosed in three dogs with signs of myelopathy. The clinicopathologic features of ISCM in these and previously reported cases in the veterinary and human literature were compared. Myelopathic signs associated with ISCM may be the initial clinical manifestation of malignancy or may develop in the patient with known malignancy. Pain, a frequent manifestation of extradural compressive myelopathy, is not a consistent feature of ISCM. Survey spinal radiographs are usually unrewarding and cerebrospinal fluid (CSF) abnormalities nonspecific. Myelography is indicated to differentiate intramedullary lesions from more common extradural compressive lesions. Myelographic interpretation may be difficult, and intramedullary tumors must be differentiated from spinal cord edema or hemorrhage. Evidence of widely disseminated malignancy should increase suspicion for ISCM; hemangiosarcoma and lymphosarcoma should be considered the most likely histologic types. CSF cytology may be helpful in the diagnosis of patients with lymphosarcoma. Prognosis is poor due to the frequent presence of disseminated disease, although temporary response to corticosteroid therapy may be achieved. More aggressive therapeutic approaches, such as spinal irradiation and microsurgical resection of metastases, have been advocated in humans but have not been reported in the dog. Although it is an uncommon complication of systemic malignancy, ISCM should be considered in the differential diagnosis of myelopathy in the dog.
The avian sarcoma virus 16 (ASV 16) is a retrovirus that induces hemangiosarcomas in chickens. Analysis of the ASV 16 genome revealed that it encodes an oncogene that is derived from the cellular gene for the catalytic subunit of phosphoinositide 3-kinase (PI 3-kinase). The gene is referred to as v-p3k, and like its cellular counterpart c-p3k, it is a potent transforming gene in cultured chicken embryo fibroblasts (CEFs). The products of the viral and cellular p3k genes have PI 3-kinase activity. CEFs transformed with either gene showed elevated levels of phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate and activation of Akt kinase.
Vascular endothelial cells are a target for blood-borne pathogens which may affect their integrity and thromboresistant properties. Here, we report that cultured bovine and human endothelial cells lose their thromboresistance following interaction with the avian hemangioma-inducing retrovirus. We show that the envelope (env) gene product, glycoprotein 85, is responsible for this effect, which appears soon after infection without viral replication or cell transformation. Induction of thrombogenicity is associated with a reduction in prostacyclin release and increased expression of tissue factor. These observations may explain the occurrence of thrombosis frequently observed in association with the hemangiosarcomas induced by avian hemangioma-inducing retrovirus. These unique endothelial cell-virus interactions may also be a model for the pathogenesis of various vascular diseases.