Canine Hemangiosarcoma

Chapter 88

Canine Hemangiosarcoma

A highly malignant tumor of endothelial cells, hemangiosarcoma (HSA) is diagnosed more frequently in dogs than in any other domestic species and is associated with a high fatality rate. Accounting for approximately 2% of all canine tumors, HSA tends to affect older dogs of either gender, with a median age of 10 years at diagnosis. Although dogs of any breed can develop HSA, German shepherds, golden retrievers, and other large or giant breeds appear predisposed.


The definitive etiology of canine HSA remains uncertain, although the strong breed association suggests that heritable factors are present to explain this genetic predisposition, and in fact gene expression phenotypes were shown to vary in HSA cells from different breeds in a recent study (Tamburini et al, 2009). Long-term ultraviolet light exposure is a known risk factor for superficial (dermal) HSA in lightly pigmented short-haired breeds of dogs and appears also to be a risk factor for HSA in the conjunctival location.

Research has shown overexpression of the oncoprotein STAT3 (signal transducer and activator of transcription 3) to be common in canine HSA. Inactivating mutations in the tumor-suppressing genes p53 and PTEN were demonstrated in canine HSA and also may contribute to the malignant transformation of vascular endothelial cells.

Angiogenesis, the formation of new blood vessels, is a tightly regulated and balanced process in homeostasis, involving both proangiogenic and antiangiogenic factors. Levels of vascular endothelial growth factor (VEGF), one of the most potent angiogenic factors, were higher in the plasma and effusions of dogs with HSA than in healthy dogs. Furthermore, increased expression of the VEGF receptor 1 (VEGFR1) gene recently was demonstrated in HSA cells obtained specifically from golden retrievers. Evidence derived from in vitro research suggests that HSA cells are capable of producing a plethora of angiogenic factors, including VEGF and basic fibroblastic growth factor (bFGF). Matrix metalloproteinases, which play a role in the breakdown of the extracellular matrix, have been shown to be active in canine HSA.

With the advent of platforms enabling evaluation of global gene expression, it soon may be possible to identify which genes and pathways are dysregulated in HSA. One recent study noted differences between HSA cells and nonmalignant endothelial cells in regard to increased expression of genes involved in inflammation, angiogenesis, adhesion, invasion, metabolism, cell cycle, signaling, and patterning. Importantly, this “signature” not only reflected a cancer-associated angiogenic phenotype but could distinguish HSA from other nonendothelial, angiogenic bone marrow–derived tumors such as lymphoma, leukemia, and osteosarcoma (Tamburini et al, 2009, 2010).

Biologic Behavior and Prognosis

Canine HSA can develop anywhere in the body. The four most common primary sites are the spleen, heart (right atrium or auricle), skin or subcutaneous tissues, and liver. Other reported primary sites include kidney, muscle, bone, oral cavity, bladder, and lung. Metastatic dissemination and local infiltration occur early in disease, either hematogenously or via local seeding following tumor rupture. The lungs, liver, and omentum are the most frequent sites of dissemination, but HSA also is recognized as the most common sarcoma to metastasize to the central nervous system (CNS). Certain primary tumor locations may predict a better prognosis, and dermal, conjunctival, and possibly subcutaneous HSA tend to have a lower metastatic rate than visceral locations. Studies have demonstrated that higher clinical stage (Box 88-1) results in earlier metastasis and shorter survival time for splenic and cutaneous HSA. When advanced metastatic disease is present, it is sometimes impossible to identify the primary site, and the prognosis is unsurprisingly poor to grave, even though occasional responses to therapy have been observed.

Diagnosis and Staging

Since clinical stage affects prognosis and HSA is a highly metastatic cancer, complete clinical staging is highly recommended at diagnosis when the patient is in sufficiently stable condition. In cases in which emergency surgical intervention is mandatory to save the patient’s life, certain diagnostic tests may need to be postponed temporarily. As previously mentioned, metastatic disease frequently affects the lungs, liver, and omental surfaces and occasionally affects the soft tissues, adrenal glands, and CNS. Although it is not considered to be true metastatic dissemination, it is known that dogs occasionally may have HSA affecting multiple primary sites (e.g., spleen plus right atrium) at presentation, a condition known as synchronous disease.

As a result, complete clinical staging ideally should include three-view high-detail thoracic radiography, abdominal ultrasonography, and echocardiography, in addition to standard blood studies. Although the typical appearance of measurable pulmonary metastatic disease is that of a coalescing miliary pattern, nodular or generalized miliary interstitial patterns also can be observed on occasion (Figure 88-1). Abdominal ultrasonography is a fairly sensitive routine imaging technique permitting the detection of splenic or hepatic lesions (Figure 88-2) and occasionally of omental nodules as well, and in most cases will identify free abdominal fluid when present. Early experience of the use of contrast-enhanced ultrasonography suggest that this technique may become more common in the veterinary setting; when the echogenicity of hepatic nodules is evaluated during arterial and parenchymal phases of contrast enhancement, malignant tumors can be differentiated from benign nodules with high rate of accuracy. Echocardiography remains the method of choice to identify right atrial masses, and these are better observed when at least some amount of pericardial effusion is present. Although urinalysis and serum biochemical studies rarely help in the diagnosis of HSA, the complete blood cell count typically shows changes that may suggest a microangiopathic process, including regenerative anemia, thrombocytopenia, and fragmented red blood cells (schistocytes). In addition, when the spleen is affected severely, a deficient reticuloendothelial system allows higher numbers of metarubricytes (nucleated red blood cells) to be observed in the circulation and on manual blood smears.

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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Canine Hemangiosarcoma

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