A Review of Proliferative Vascular Disorders of the Central Nervous System of Animals.

In disease, blood vessel proliferation has many salient roles including in inflammation, when granulation tissue fills superficial defects, or in the recanalization of an occluded blood vessel. Sometimes angiogenesis goes awry-granulation can be exuberant, and plexiform proliferation of vascular components can contribute to pulmonary hypertension. This review focuses on the diverse manifestations of pathologic vascular overgrowth that occur in the brain, spinal cord, and meninges of animals from birth until old age. Entities discussed include systemic reactive angioendotheliomatosis in which glomeruloid vascular proliferations are encountered in various organs including the central nervous system (CNS). The triad of CNS vascular malformations, hamartomas, and benign vascular proliferations are an especially fraught category in which terminology overlap and the microscopic similarity of various disorders makes diagnostic classification incredibly challenging. Pathologists commonly take refuge in "CNS vascular hamartoma" despite the lack of any unique histopathologic features and we recommend that this diagnostic category be abandoned. Malformative lesions that are often confusing and have similar features; the conditions include arteriovenous malformation, cavernous angioma, venous angioma, and capillary telangiectases. Meningioangiomatosis, a benign meningovascular proliferation with dual components, is a unique entity seen most commonly in young dogs. Last, accepted neoplastic conditions range from lower-grade locally acquired growths like hemangioblastoma (a tumor of mysterious interstitial stromal cells encountered in the setting of abundant capillary vasculature proliferation), the rare hemangioendothelioma, and the highly malignant and invariably multifocal metastatic hemangiosarcoma. Additionally, this review draws on the comparative medical literature for further insights into this problematic topic in pathology.

IMAGING DIAGNOSIS-MAGNETIC RESONANCE IMAGING FINDINGS IN A CAT WITH SYSTEMIC REACTIVE ANGIOENDOTHELIOMATOSIS.

A 10-year-old, castrated male domestic short-haired cat was presented with an acute history of seizures, lethargy, anorexia, vomiting, and dyspnea. Magnetic resonance imaging of the brain showed multifocal areas of gray matter T2-weighted hyperintensity. The lesions did not enhance with intravenous contrast. The cat was diagnosed at necropsy with feline systemic reactive angioendotheliomatosis, a rare vascular proliferative disorder for which a treatment has not yet been identified. This report is the first to describe associated magnetic resonance imaging changes for this disease.

Neck Kaposiform haemangioendothelioma in a Fischer's lovebird (Agapornis fischeri).

A six-year-old female Fischer's lovebird (Agapornis fischeri) presented at necropsy with a cutaneous mass on the neck, 3.5cm in diameter, yielding and with blood content. Histopathological findings showed a neoplasm characterized by proliferation of vascular endothelial cells. The histology of the mass revealed a multinodular, focally infiltrating tumor. Deeper dermal nodules were made of spindle cells forming vascular slits reminiscent of the histology seen in Kaposi's sarcoma (KS). More superficially located dermal nodules consisted of small blood vessels, with histology resembling capillary hemangioma. The spindle cells and capillaries were strongly positive for Vimentin, endothelial cell marker CD31, and negative for sarcomeric α-smooth muscle actin (α-SMA). Intravascular platelet trapping and Periodic acid-Schiff (PAS)-positive hyaline globules were also observed. Differential diagnosis included Kaposi's sarcoma, capillary haemangioma, spindle cell haemangioendothelioma, and epithelioid haemangioendothelioma. Based on morphological and immunohistochemical findings, the tumor was diagnosed as a cutaneous Kaposiform haemangioendothelioma (KHE), a rare, low-grade malignant vascular neoplasm. Other organs showed no abnormalities. PCR amplifications, conducted using Kaposi's sarcoma-associated herpesvirus (KSHV)-specific primers and degenerate sets of primers designed to detect and characterize members of the Herpesviridae, on DNA extracted from tumor tissue and from whole blood failed to amplify any KSHV-related sequence. Moreover, no specific signal was obtained using primers for detection of psittacine herpesvirus, known to be linked to Pacheco's disease in parrots. To the best of our knowledge, this unusual case is the third report of KHE in a non-human animal species, the first described in a bird.

Two canine malignant vascular tumours with features of human retiform haemangioendothelioma.

Within the human medical literature, retiform haemangioendothelioma (RHE) is an established and well-recognized histopathological variant of endothelial tumours, but to date RHE has not been reported in animals. These tumours are characterized by the presence of elongate, arborizing vascular channels lined by neoplastic endothelium with prominent, often bulging ('hobnail') nuclei supported by a dense collagenous matrix and accompanied by abundant lymphoplasmacytic inflammation. Immunohistochemically, the neoplastic cells typically express endothelial markers such as von Willebrand factor and CD31. Human RHEs are categorized as low-grade malignancies. This report describes two canine vascular tumours with features consistent with RHE. In both cases there was suspected or known widespread tumour metastasis.

Massive haematoma formation associated with proximal popliteal artery haemangioendothelioma in a dog.

A mixed breed dog presented with diffuse unilateral hind limb swelling, which ultrasound and cytology confirmed to be caused by severe haematoma formation. Multi-detector computed tomography (MDCT) angiography allowed distinct visualisation of an anomalous segment of the proximal popliteal artery, the presumed origin of the self-sustaining haematoma. Histopathology classified the malformed vessel as a haemangioendothelioma, a neoplasia of intermediate malignancy. Considering this as differential diagnosis to a neoplastic vascular alteration of high malignancy (such as haemangiosarcoma) might alter choice of treatment in future cases with similar clinical and imaging findings.

Kaposi-like vascular tumor of the urinary bladder in a cow.

Kaposiform hemangioendothelioma is a rare human vascular neoplasm. In veterinary medicine this tumor type was only recognized in the dog. Here we describe an unusual case arising in the urinary bladder of a Holstein-Friesian adult cow. Histologically the tumor presented a nodular proliferation of spindle cells, forming angular slits, often containing extravasated erythrocytes. Peripherically, well-formed vascular channels were seen. These cells were positive to vimentin and to factor VIII-related antigen by immunohistochemical stain. Based on its characteristics, it was classified as kaposiform hemangioendothelioma and as far as we know, it is the first case described in cattle.

Canine vascular neoplasia--histologic classification and inmunohistochemical analysis of 221 tumours and tumour-like lesions.

A light microscopic evaluation of 221 canine vascular tumours and tumour-like lesions, supplemented by immunohistochemistry (von Willebrand Factor, CD31, vimentin), revealed a high degree of conformity with similar conditions in humans. Four main categories of tumours are reported, i.e. benign types: haemangiomas (n=127) and lymphangioma (n=1); tumour-like lesions: papillary endothelial hyperplasia (n=8) and vascular ectasias (n=2); neoplasms of intermediate malignancy: haemangioendotheliomas (n=27), and the obvious malignant form: angiosarcomas (n=57). Further classification showed that all subtypes had their human counterparts. Papillary endothelial hyperplasia and arteriovenous and venous haemangiomas are described for the first time in dogs. The combination of conventional histopathologic methods and immunohistochemistry was in many cases very useful diagnostically, the latter technique being in some cases indispensable for establishing a definite diagnosis. In general CD31 was the most useful marker for tumours originating from endothelial cells, especially for poorly differentiated haemangiosarcomas.

Kaposiform hemangioendothelioma: the first reported case in a nonhuman animal species.

Kaposiform hemangioendothelioma is a rare vascular tumor that almost exclusively occurs in children. It is a low-grade malignant neoplasm that is locally aggressive but without proven metastatic potential. Herein, we describe a case of Kaposiform hemangioendothelioma in a 10-year-old male dog. To the best of our knowledge, this is the first report of this vascular tumor occurring in a nonhuman animal species. The tumor was located on the ventromedial surface of the posterior limb. Microscopic examination of the lesion revealed a multinodular tumor with sheets of spindled endothelial cells forming vascular slits similar to Kaposi's sarcoma and peripheral tumor lobules resembling capillary hemangioma.

Combretastatin family member OXI4503 induces tumor vascular collapse through the induction of endothelial apoptosis.

The mechanism of tumor cell killing by OXI4503 was investigated by studying vascular functional and morphological changes post drug administration. SCID mice bearing MHEC5-T hemangioendothelioma were given a single dose of OXI4503 at 100 mg/kg. Tumor blood flow, measured by microsphere fluorescence, was reduced by 50% at 1 hr, and reached a maximum level 6-24 hr post drug treatment. Tumor vascular permeability, measured by Evan's blue and hemoglobin, increased significantly from 3 hr and peaked at 18 hr. The elevated tumor vessel permeability was accompanied by an increase in vascular endothelial growth factor (VEGF) from 1 hr post drug treatment. Immunohistochemical staining for CD31 and laminin showed that tumor blood vessels were affected as early as 3 hr but more prominent from 6 hr. From 12 hr, the vessel structure was completely destroyed. Histopathological and double immunohistochemical staining showed morphological change and induction of apoptosis in endothelial cells at 1-3 hr, followed by tumor cell necrosis from 6-72 hr. There were no statistically significant changes of Evan's blue and hemoglobin contents in liver tissue over the time course. These results suggest that OXI4503 selectively targets tumor blood vessels, and induces blood flow shutdown while it enhances tumor blood vessel permeability. The early induction of endothelial cell apoptosis leads to functional changes of tumor blood vessels and finally to the collapse of tumor vasculature, resulting in massive tumor cell necrosis. The time course of the tumor vascular response observed with OXI4503 treatment supports this drug for development as a stand alone therapy, and also lends support for the use of the drug in combination with other cancer therapies.

Invading and metastasizing cardiac hemangioendothelial neoplasms in a cohort of the fish Rivulus marmoratus: unusually high prevalence, histopathology, and possible etiologies.

An unusually high, unprecedented prevalence of cardiac hemangioendotheliomata, including hemangiomas, hemangioendotheliomas, and hemangioendotheliosarcomas, was found in a laboratory cohort of the small, teleost fish Rivulus marmoratus. The neoplasms occurred in 51 of 204 fish (25%) used in a carcinogenicity study of butylated hydroxyanisole fed in a lyophilized chicken liver diet for up to 9 months. The cardiac neoplasms occurred in approximately equal numbers of both control (fed lyophilized chicken liver but not exposed to butylated hydroxyanisole) and exposed (fed 0.8% butylated hydroxyanisole in chicken liver) fish. The neoplasms occurred in the bulbus arteriosus and ventricle (accompanied by an intense epicarditis), and in some cases, in the gills. At least one case of hemangioma was characterized by cavernous vessels in the bulbar wall. Hemangioendothelioma cases consisted of pleomorphic endothelial cells that formed continuous tracts and anastomosing, typical vascular channels of varying sizes. The hemangioendotheliosarcomas consisted of atypical, spindle, polygonal, or round endothelial cells that formed solid tumor masses that contained abnormal vessels with atypical endothelium tufting into their lumina. Some fish had neoplasm cases containing varying regions with mixtures of the above features. Incipient neoplasms occurred on/in the semilunar valves, and their cells appeared to invade the adjacent walls of the bulbus and/or the ventricle. The gill lesions represented possible metastatic neoplasms, probably formed by atypical endothelial cells that exfoliated from the edges of cardiac neoplasms into the lumina of the ventricle or bulbus and were then pumped to the arterioles of the gills via the ventral aorta. Fish examined from the original colony in the laboratory and from the wild had no neoplasms. Possible causes are discussed, and studies are under way in an attempt to determine the etiology of the neoplasm and to evaluate Rivulus marmoratus as a possible model organism for study of these types of cardiac neoplasms.

Cytogenetic analyses of four solid tumours in dogs.

Four solid tumours (one haemangiopericytoma, one haemangioendothelioma, one spindle-cell sarcoma and one mammary carcinoma) in dogs were analysed cytogenetically. In the haemangiopericytoma, an additional small chromosomal segment was present. Very complex changes including centric fusions and symmetric meta-centrics 1, 6, 10 and 12 were conspicuous in the highly unbalanced karyotype of the haemangioendothelioma. Complex changes, particularly many centric fusions and a tandem translocation 4/14, were features of the spindle-cell sarcoma. One centric fusion and a symmetric metacentric 13 were present in the mammary carcinoma.

Two haemangioendotheliomas in a bovine brain.

The microscopical, ultrastructural and immunohistochemical features of an unusual type of haemangioendothelioma in the brain of a calf are described. The salient features of this tumour were an exuberant proliferation of vasoformative elements whose endothelial cells exhibited epithelioid and spindle cell features. Intracytoplasmic miniature lumen formation in endothelial cells was characteristic of this vascular neoplasm.

Cytogenetic analysis of a canine haemangioendothelioma: a case report.

An 8-year-old German Shepherd bitch developed a haemangioendothelioma in the mammary region. The cytogenetic characterization of the tumour cells revealed a chromosome number of 80 plus a double minute. Several aberrations were detected: trisomies 4, 35, and 38, a centric fusion 8/22 and a tandem translocation 9/23.

Neoplastic angioendotheliomatosis in a dog: an angiotropic lymphoma.

Neoplastic angioendotheliomatosis was diagnosed in a nine-year-old, intact male German Shorthaired Pointer exhibiting progressive neurological signs over a six-month period. At necropsy, there was multifocal asymmetric, hemorrhagic necrosis within the cerebral hemispheres, centrum semiovale, caudate nucleus, and internal capsule. Histologically, there was extensive intravascular proliferation of pleomorphic mononuclear cells within the brain and multiple parenchymatous organs. Transmission electron microscopy demonstrated the absence of intercellular junctions between neoplastic cells. These cells were not attached to the vascular lining endothelium; Weibel-Palade bodies and a basement membrane were lacking. By indirect immunofluorescence, positive cytoplasmic staining of intravascular neoplastic cells for IgG was demonstrated. Peroxidase-antiperoxidase technique for Factor VIII related antigen was negative. As in man, this rare neoplastic disorder appears to be a lymphoma, apparently of the B cell line.

[Incidence, primary site and pattern of metastasis in hemangioendothelioma in the dog. An evaluation of autopsy material from 1970 to 1985]. / Vorkommen, Primärsitz und Metastasierungsmuster des Hämangioendothelioms beim Hund. Eine Auswertung des Sektionsmaterials aus den Jahren 1970 bis 1985.

In 16 years 13,869 dogs were autopsied. Angiosarcomas were found in 321 cases (2.3%). The frequency has increased since 1981 and was doubled. Alsations and boxers were found to have a statistically significant predisposition. Dogs affected with this tumor were between 3 and 15 years old, the average being 9.4 years. The tumour could more frequently be found in male dogs than in bitches. Primary localizations were mainly spleen, heart, or liver. Haematogenous metastases were very common, in some cases a primary multiplicity was supposed. The distribution of the metastases depended on the organ primarily involved.

Cerebral angioendotheliomatosis in a dog.

A 6-year-old dog which presented with weakness of the hind limbs progressed to a cerebral disorder with altered sensorium. The cerebrospinal fluid (CSF) protein was elevated, but no cells were found. Autopsy revealed severe hemorrhages in the basal nuclei and diencephalon. Histology of the lesions showed many meningeal and parenchymal blood vessels filled with neoplastic mononuclear cells. Electron microscopy of the tumor cells demonstrated ribosomes, granular endoplasmic reticulum, mitochondria, and a few lysosomes. Immunocytochemical procedures to demonstrate Factor VIII-related antigen were negative. This appears to be the first recorded case of cerebral angioendotheliomatosis in domestic animals and closely resembles the syndrome in man.