Introduction

Hemangiosarcoma (HSA) is an aggressive malignancy formed in the vascular endothelial lining of blood and lymphatic vessels.

Etiology and Pathophysiology

The set of causes for malignant HSA is unknown; however, research shows that dysregulated angiogenic pathways and bone marrow stem cells are involved in its development. In addition, solar radiation exposure to dog breeds with short, thin coats that lack pigment are at greater risk for developing cutaneous, subcutaneous, and muscular forms. Specifically, geriatric dogs between the ages of 9–12 years are most affected, and there is no sex predilection. However, anecdotally males may be more affected. Breeds predisposed to HSA include golden retrievers, German shepherd dogs, Labrador retrievers, boxers, and Portuguese water dogs. Due to the increased risk in these breeds, a familial or genetic component may be involved.¹ According to the Golden Retriever Health Study (in cooperation with the Morris Animal Foundation), an estimated 1 in 5 golden retrievers have a lifetime risk of developing HSA. HSA also affects cats, but the prevalence is less than in dogs. In studies evaluating large populations of cats, only 1.1–1.7% of the population were diagnosed with either the visceral or cutaneous form of HSA. The visceral form is highly metastatic in cats and carries a guarded prognosis.

The three most common sites associated with HSA in dogs include the spleen (50%), right atrium and auricle (25–50%), and the skin or subcutaneous tissue (15%). Approximately 25% of dogs with HSA have it in both the spleen and heart. HSA has been reported in the right ventricular free wall, interventricular septum, and main pulmonary artery.² Other primary sites include bone, oral cavity, bladder, kidneys, and muscle. Metastatic sites that are seeded from ruptured tumors include the liver, lung, omentum, and the central nervous system.³

The biologic behavior of the visceral form of HSA is quite different from the cutaneous form. Cutaneous and subcutaneous hemangiomas (HA) are benign tumors. Cutaneous HSA is a malignant tumor less aggressive in the dermal layer than those located in the subcutaneous layer or muscle. Breeds associated with cutaneous HA and HSA include whippets, dalmatians, greyhounds, pit bulls, Italian greyhounds, beagles, bull terriers, English pointers, and basset hounds.

Clinical Features

Dogs with visceral HSA may be completely asymptomatic until they present with signs associated with acute rupture of the primary tumor (resulting in hemoperitoneum), metastases, cardiac arrhythmias, and/or coagulopathies. Clinic signs include inappetence, lethargy, weakness, or collapse, very pale to white gums, rapid/shallow breathing, and sudden death.

Cutaneous HA and HSA present as singular or multiple red to purple nodules and are in the areas of the skin where the hair is sparse or thin and lightly pigmented. The ventral abdomen, prepuce, scrotum, and distal limbs are the most affected areas. For example, dogs that “sunbathe” and lie on their backs or sides while outdoors. In cats, light-colored pinnae are more at risk. Additionally, in both dogs and cats, these tumors are not painful. Subcutaneous and muscular involvement of HA and HSA typically involves a single mass. These can vary in size from small to quite large, that bruise and bleed easily. The masses have areas of necrosis and ulceration and are commonly painful when palpated.⁴

Diagnosis

Diagnosis of visceral and cutaneous HSA consists of clinical history, clinical findings, and staging.

HSA staging includes:

• CBC
• Blood smear evaluation for schistocytes, acanthocytes, thrombocytopenia, leukocytosis, monocytosis
• Chemistry profile noting hypoalbuminemia, elevated hepatic enzymes, elevated AST in cats
• Urinalysis
• Clotting profile noting increased clotting times/DIC
• 3-view radiograph for metastases and cardio involvement
• Abdominal ultrasound with hepato-splenomegaly and other visceral involvement
• Echocardiogram for patients suspected of having right atrial involvement

Cytology of the mass or pleural affusion tends to yield small numbers of mesenchymal cells, making it challenging to obtain a conclusive diagnosis, due to the poor exfoliation of mesenchymal cells. Therefore, the definitive diagnosis of HSA requires histopathologic confirmation.

Treatment

Surgery followed by adjuvant chemotherapy is the standard of care. Chemotherapy includes single-agent doxorubicin and various combinations of doxorubicin, vincristine, cyclophosphamide, or lomustine, and metronomic chemotherapy. In addition, NSAIDs and tyrosine kinase inhibitors (toceranib) are also used along with chemotherapy.

In addition, propranolol acting as a chemosensitizer with doxorubicin is under clinical evaluation. Beta-adrenergic receptor antagonists (beta-blockers) increase the level of doxorubicin in cancer cells. Propanol increases the capability of doxorubicin to damage the DNA of HSA cells and inhibits the efflux of doxorubicin from the cell, thus allowing for increased tumor cell destruction.⁵

Although controversial, the Chinese herb Yunnan Baiyo and the proprietary polysaccharopeptide (PSP) Trametes Versicolor (Turkey Tail mushrooms) have anecdotally shown to be beneficial.⁶

Prognosis

Even with treatment, virtually all patients diagnosed with visceral HSA will succumb to their disease.

Table 1.1 Surgery + chemotherapy

Table 1.2 Surgery alone

Future Diagnostics

HSA biomarker profiles from ongoing studies show increased plasma levels of VEGF and serum endothelin-1 in dogs diagnosed with HSA compared to dogs in control groups. Other markers include angiopoietin-2, platelet-derived growth factor (PDGF), and basic fibroblast growth factor s(bFGF).⁷

When cardiac involvement is suspected, elevated plasma levels of cardiac troponin l (cTnl) are noted. Using plasma cTnl may allow for earlier cardiac HSA in dogs having HSA in other parts of the body (skin, liver, bone) and cardiac HSA in dogs with pleural effusion.⁸

Thymidine kinase type 1 (TK1) is an enzyme selectively restricted to proliferating cells and is elevated in patients with HSA.⁹

Collagen XXVII peptide is a by-product of a protein involved in invasive and angiogenesis activities and has shown to be elevated in dogs with HSA.¹⁰

Summary

The hope is that with forthcoming biomarker diagnosis, earlier detection, and combined with better-targeted treatment options, HSA patients may enjoy a better quality of life and longer remission times.

References

1.  Clifford CA, Mackin MJ, Henry CJ. Treatment of canine hemangiosarcoma: 2000 and beyond. J Vet Intern Med. 2000;14:479–485.

2.  Veterinary Society of Surgical Oncology. Hemangiosarcoma.

3.  Snyder JM, Lipitz L, Skorupski KA, Shofer FS, Van Winkle TJ. Secondary intracranial neoplasia in the dog:177 case (1986–2003). J Vet Intern Med. 2008;22(1):172–177.

4.  Holm K, Smrkovski O, Waltman SS. Hemangioma/Hemangiosarcoma, Cutaneous & Subcutaneous. VINcycopedia. Last updated 11/10/2020.

5.  Saha J, et al. Propranolol sensitizes vascular sarcoma cells to doxorubicin by altering lysosomal drug sequestration and drug efflux. Front Oncol. 2020;10:614288.

6.  Benson KF, et al. The mycelium of the Trametes versicolor (Turkey tail) mushroom and its fermented substrate each show potent and complementary immune activating properties in vitro. BMC Complement Altern Med. 2019;19:42.

7.  Kakiuchi-Kiyota S, et al. Expression of hematopoietic stem and endothelial cell markers in canine hemangiosarcoma. Toxicol Pathol. 2020;48(3):481–493.

8.  Chun R, Kellihan HB, Henik RA, Stepien RL. Comparison of cardiac troponin I concentrations among dogs with cardiac hemangiosarcoma, noncardiac hemangiosarcoma, other neoplasms, and pericardial effusion of nonhemangiosarcoma origin. J Am Vet Med Assoc. 2010;237(7):806–811.

9.  Thamm DH, Sharp CR, et al. Elevated serum thymidine kinase activity in canine splenic hemangiosarcoma. Vet Comp Oncol. 2012;10(4)292–302.

10.  Kirby GM, et al. Concentration of lipocalin region of collagen XXVII alpha 1 in the serum of dogs with hemangiosarcoma. J Vet Intern Med. 2011;25(3):497–503.