Hemangiosarcoma (HSA) is a highly malignant tumor arising from endothelial cells. These cells are derived from bone marrow precursors and can develop lesions in any tissue containing vascular structures1–3.
HSA is a very common tumor in dogs representing 2% of all cancers and more than 50% of all splenic malignancies in the species4–7. Although all breeds can be affected, there is higher predisposition for male large breed dogs, such as German Shepherds, Golden Retrievers and Labrador Retrievers, especially middle-aged to older dogs (~10 years old)6,8,9.
Over the last two years, FidoCure® has sequenced 190 splenic and 56 non-splenic hemangiosarcoma cases. The most common breeds identified in this dataset were in agreement with the literature: German Shepherd, Labrador Retriever, Golden Retriever, and American Pit Bull Terrier (Figure 1). Spay/neuter status and genetic abnormalities are also associated with all canine HSA development, while cutaneous HSA is also associated with ultraviolet light exposure3, 10–14.
HSA can develop in any tissue or structure of the body. Common sites include spleen, heart, liver, and skin. Other less common sites described in the literature are kidney, retroperitoneal space, muscle, bone, eye, conjunctiva, oral cavity, urinary bladder, digit, mediastinum and lungs3,7. Visceral HSA is more common than dermal HSA and is associated with a poorer prognosis due its highly metastatic nature. HSA metastasis can occur via hematogenous dissemination or intracavity implantation. Liver, omentum, lungs and brain are commonly affected by metastatic lesions3, 7, 15 ,16.
Dogs with visceral HSA generally present with nonspecific clinical signs usually associated with primary tumor development. These can include anorexia, weight loss, pale mucous membranes, tachycardia, cardiac arrhythmias, weak pulses, tachypnea, dyspnea, abdominal distention, organomegaly and palpable fluid wave. Some dogs can have internal hemorrhage due to tumor rupture3,6,11,12,17–20.
Histopathology examination is the gold standard for a definitive diagnosis of HSA. However, most cases are taken to surgery without a confirmed diagnosis based on clinical signs, ultrasound findings, and/or presence of non-clotting blood in the abdomen3,21,22. Clinical staging is necessary to evaluate the true extent of the disease and often is governed by how stable the patient is at presentation. CBC, biochemistry, coagulation profiles, urinalysis, three-view thoracic radiographs, abdominal ultrasound and echocardiography are usually recommended to complete the TNM staging. Common hematological alterations include regenerative anemia with schistocytes, acanthocytes and nucleated red blood cells; thrombocytopenia; neutrophilic leukocytosis; prolongation of prothrombin and partial thromboplastin time; increased fibrinogen and positive d-dimers7,19,26–29. CT scan and MRI can also be performed to better identify small tumor lesions and early metastases3,7.
Some studies have shown potential HSA-specific biomarkers such as cardiac troponin I, serum collagen XXVII peptide and thymidine kinase, but they have been mainly used for research purposes23–25.
The standard treatment for dogs with HSA is surgery, typically involving a splenectomy. Dogs with hypovolemic shock, pericardial effusion or a severe anemia need to be stabilized prior to surgery17,30–33. Systemic therapy is usually recommended after surgery due to the aggressive tumor behavior and high metastatic rate of HSA. Doxorubicin is the most widely used chemotherapy agent and can be used as a single agent or in combination with vincristine, cyclophosphamide, dacarbazine, ifosfamide or thalidomide31,34–41. Epirubicin may be as effective as doxorubicin and is considered an option for patients with cardiac disease due to its decreased risk for cardiotoxicity42.
Metronomic cyclophosphamide and chlorambucil with or without NSAIDs are also an alternative of systemic therapy for canine HSA43,44. In addition, other treatments involving targeted therapy and immunotherapy have been evaluated to improve survival time and better clinical responses, such as toceranib phosphate (inhibitor of tyrosine kinase receptors KIT, PDGFR and VEGFR), eBat (bispecific epidermal growth factor-urokinase angiotoxin) and liposomal muramyl tripeptide phosphatidylethanolamine (L-MTP-PE)45–49.
In some cases of subcutaneous/intramuscular and cardiac HSA, local palliative care with hypofractionated radiotherapy can also be successfully performed with a high response rate. Although this treatment may not improve the survival time of dogs with cardiac HSA, it can still be recommended to avoid cardiac tamponade50,51.
Despite aggressive treatment, canine HSA still carries a poor prognosis with median survival times varying from 2 weeks to 9 months for visceral HSA and 9 months to 3 years for dermal HSA17, 31–33, 52–56.
Germline and Somatic Mutations
Alterations at the genomic level may reveal differences between different forms of canine HSA. Germline mutations are associated with hereditary risks of cancer development, especially for HSA in Golden Retrievers. On the other hand, somatic mutations directly contribute to tumor growth and progression, commonly referred to as driver mutations, and are responsible for canine HSA development (Figure 2)13,57,58.
Coming soon...Part 2 featuring our genomic sequencing results from 246 Hemangiosarcoma tumors UPDATE: Part 2 is available here
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