Hemangiosarcoma: Look for endothelial precursors as sign

Hemangiosarcoma: Look for endothelial precursors as sign

Feb 01, 2006

Q. Please review new concepts in diagnosing and managing hemangiosarcoma in dogs.

A. Drs. Angela R. Lamerato-Kozicki and Jaime F. Modiano at the 2005 American College of Veterinary Internal Medicine Forum in Baltimore gave a lecture on early detection of hemangiosarcoma. Some relevant points in this lecture are provided below.

Canine hemangiosarcoma (HSA) is an incurable tumor of vascular endothelial cells. HSA accounts for 7 percent of all cancers; thus, of the 65 million pet dogs living in the United States today, between 1.5 million and 2.5 million could get HSA and succumb to it. Although dogs of any age and breed are susceptible to HSA, it occurs more commonly in dogs beyond middle age and in breeds such as Golden Retrievers, German Shepherds, Portuguese Water Dogs and Skye Terriers. The estimated life-time risk of HSA in Golden Retrievers is one in five, illustrating the magnitude of this problem.

The common primary sites for HSA are spleen, right atrium and subcutis. Local infiltration and systemic metastases are the common growth patterns; metastatic sites are widespread with lung and liver being the most frequently affected organs.

The disease is extremely indolent, so clinical signs are usually not evident until the advanced stage when metastasis has occurred. The tumors at this stage are largely resistant to chemotherapy, and standard-of-care (surgery and intensive chemotherapy) provides a median survival of little more than six months. Morbidity and mortality are usually due to acute internal hemorrhage secondary to tumor rupture. Many dogs die from severe abdominal or thoracic hemorrhage before any treatment can be instituted.

There is presently no effective technology for early diagnosis of HSA. Careful examination of blood smears may hint at the presence of chronic hemorrhage (anemia and thrombocytopenia) and vascular abnormalities (red blood cell fragmentation) that are consistent with HSA; however, this method is neither sensitive nor specific to confirm the diagnosis. Non-invasive imaging methods are useful aids to diagnose the disease (for cavitary tumors such as those that occur in the spleen or heart). Ultrasound is moderately specific, but it is not sensitive.

Moreover, biopsies are required for confirmation of imaging results, and even then, distinction between hemangiosarcoma and benign lesions (hemangioma, hematoma) can be difficult. Skin biopsies where there is no lesion would be of little use to provide early diagnosis for cutaneous HSA. The same is true for splenic, hepatic or cardiac tumors with the added issue that the risk of these procedures in the absence of a visible tumor (on radiographs or ultrasound) is unacceptable. Given the severity of canine HSA and the lack of effective treatment options for advanced disease, it would be useful to have a method for early detection, which might improve the outcome of dogs treated with standard-of-care as well as the design of novel treatment options that may have a better chance of eradicating the tumor.

The endothelial origin of HSA characterizes this tumor in the broad group of hematopoietic or bone marrow-derived malignancies. Endothelial cells arise from bone marrow stromal cells that are triggered to differentiate along the hemangioblastic lineage. Hemangioblasts are pluripotent hematopoietic stem cells. Under conditions of enhanced angiogenesis, these cells give rise to angioblasts, which further differentiate into endothelial precursor cells (EPC). EPC have high proliferative capacity and are largely responsible for physiologic and pathologic angiogenesis. Limited numbers of EPC (and perhaps more primitive stem cells) are found among differentiated blood vessel lining cells in adult animals (humans and mice) and in the peripheral circulation. These cells (in humans and mice) are characterized by the expression of CD34, CD133 and the vascular endothelial growth factor (VEGF) receptor 2; however, the number of EPC in the peripheral circulation of normal individuals is virtually undetectable, except by the most sensitive methods or by prolonged expansion in vitro using specific growth conditions.

Distinguishing from benign cells