Past, Present, and Future Perspectives on Canine Hemangiosarcoma
World Small Animal Veterinary Association World Congress Proceedings, 2015
Kim A. Selting1, DVM, MS, DACVIM (Oncology), DACVR (Radiation oncology)
1College of Veterinary Medicine, University of Missouri, Columbia, MO, USA

Background (Past)

In all reported species, hemangiosarcoma is consistently portrayed as a highly aggressive, highly metastatic cancer with few exceptions. In veterinary medicine, published case series exist for dogs, cats, and horses. This solid tumor is classically considered a tumor of blood vessels, and research has suggested that these tumors develop from circulating bone marrow-derived precursors. Though this ontogeny is incompletely understood, the pathogenesis is being elucidated. Common sites of primary tumor formation include spleen, heart (right atrium or atrial appendage), and muscle or subcutaneous location. Approximately 10–30% of dogs will have concurrent involvement of heart and spleen. This is primarily a cancer of older, larger-breed dogs, but can affect any age and breed.

While subcutaneous, intramuscular, and non-splenic visceral locations all behave in a similar manner, small lesions truly confined to the epidermis have a less aggressive and less metastatic behavior. Multiple cutaneous hemangiosarcoma lesions can be seen on the non-haired ventral abdomen as a result of ultraviolet light exposure and primarily require treatment if they are growing. Survival times can exceed 2 years. However, for all other sites, median survival time for surgical resection followed by doxorubicin chemotherapy with or without other drugs is consistently around 6 months. One report found similar survival for dogs with subcutaneous versus intramuscular primary location; however, another describes prolonged (> 1100 days) median survival for subcutaneous location treated with some combination of chemotherapy with or without radiation therapy, and this was better than intramuscular location which was similar to other reports (9 months). For splenic hemangiosarcoma treated with splenectomy and no other therapy, median reported survival is only 86 days.

This cancer is similarly aggressive and metastatic in cats.

Staging

As with most sarcomas, hematogenous spread is the predominant method of metastasis. Though lymph nodes may be involved, lungs are considered the primary target. Abdominal ultrasound is used to both characterize a primary tumor if splenic in origin, and all viscera are evaluated for metastatic disease or less common primary sites. In addition, pulmonary radiographs are performed to assess affected animals for metastatic disease. At the time of surgery, liver is often sampled to screen for occult metastasis but a recent report found that visibly normal livers did not yield hemangiosarcoma.

Most dogs with hemoperitoneum and a bleeding splenic mass (75%) will be diagnosed with hemangiosarcoma, though some dogs will have hematomas. Most dogs with secondary intracranial neoplasia will have metastatic hemangiosarcoma.

Cardiac troponin I (cTnI) is a unique isoform of this subunit involved in the contractile apparatus. It is genetically distinct from TnI of skeletal or other origin and is 97% cytoskeletally bound, such that increases in its circulating concentrations exclusively represent cardiac myocyte death. Because hemangiosarcoma can occur in the heart concurrently with the spleen, cTnI concentration has been evaluated for the ability to predict cardiac involvement. Concentrations greater than 0.25 ng/ml had a 100% specificity for detecting cardiac involvement if pericardial effusion was present, though sensitivity was lower. There were dogs in that series that did not have an echocardiographically evident right atrial mass, but did have an increased cTnI and were later confirmed to have a mass in the heart.

Treatment Options and Prognosis (Present)

As noted above, the treatment of hemangiosarcoma in dogs and cats initially involves surgery when possible, followed by doxorubicin-based chemotherapy. The addition of NSAIDs for their antiangiogenic and other properties, does not seem to improve outcome over doxorubicin alone. In addition, radiation therapy can be used to improve local control, and larger fractions may have a good chance at consolidating local tumor. Progress is being made in determining the pathogenesis of hemangiosarcoma such that new therapies are being developed. Inflammation and angiogenesis are integral to the development of this tumor. Vitamin D may be low in affected animals, and supplementation may be indicated. Low vitamin D concentrations (25 hydroxyvitamin D) are associated with inflammation.

Because hemangiosarcoma is a tumor of blood vessels, metronomic chemotherapy has been considered because of its antiangiogenic effects. Receptor tyrosine kinase inhibitors that inhibit vascular endothelial growth factor receptor have been tried and are discussed further below. In addition, the nitrosourea alkylating agent lomustine (CCNU) has also been used in a metronomic fashion. Though the drug was reasonably well tolerated, approximately one third discontinued therapy due to toxicity, and median duration of treatment was just over 90 days. A few partial responses were seen and several dogs attained stable disease.

Thymidine kinase type 1 (TK1) is a soluble marker of proliferation that has been noted to be markedly increased in dogs with hemangiosarcoma. While its use in distinguishing causes of hemoperitoneum had some limitations, it could be used to monitor response to therapy.

Hope on the Horizon (Future)

Regarding etiopathogenesis, an interesting recent investigation in Golden Retrievers suggested that sex hormones or lack thereof may contribute to the risk of developing hemangiosarcoma, with female dogs neutered after one year of age at greater risk than those left intact or neutered early (before one year of age). This may lead to the elucidation of the role of sex hormones in protecting or priming cells for neoplastic transformation, which can guide rational decisions on breeding and neutering practices and may offer novel therapeutic approaches. Another unpublished study using a large database also found an association with risk of being diagnosed with hemangiosarcoma and the status of being neutered.

The tyrosine kinase inhibitor masitinib showed a dose-dependent inhibition of proliferation in hemangiosarcoma cell lines and may have value in treating this disease. Platelet-derived growth factor receptor is a target for this class of receptor tyrosine kinase receptor inhibitors, and different isoforms are associated with different anatomic locations and clinical behavior (alpha for cutaneous and beta for visceral or other), which lends support to their use in this cancer.

Gene expression profiles may allow clinicians to determine a genetic signature that predicts the behavior of a given tumor. These appear to be breed specific and show clustering of altered gene expression in sequences associated with inflammation and angiogenesis.

The possible benefit of vitamin D supplementation in decreasing cancer risk or improving response to standard therapies is unknown but relatively low risk and worthy of investigation. In addition, the supplement Yunnan Bai Yao (or Pai Yao, dosed most commonly at one capsule twice daily for an average sized dog around 20–30 kg) has been used to curb bleeding tendencies. While the mechanism of this benefit is not understood, a growing number of anecdotes describe clinical benefit and this warrants further investigation.

References

1.  Chun R, Kellihan HB, Henik RA, Stepien RL. Comparison of plasma 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.

2.  Lyles SE, Milner RJ, Kow K, Salute ME. In vitro effects of the tyrosine kinase inhibitor, masitinib mesylate, on canine hemangiosarcoma cell lines. Vet Comp Oncol. 2012;10(3):223–235.

3.  Tamburini BA, Phang TL, Fosmire SP, et al. Gene expression profiling identifies inflammation and angiogenesis as distinguishing features of canine hemangiosarcoma. BMC Cancer. 2010;10:619.

4.  Bulakowski EJ, Philibert JC, Siegel S, et al. Evaluation of outcome associated with subcutaneous and intramuscular hemangiosarcoma treated with adjuvant doxorubicin in dogs: 21 cases (2001–2006). J Am Vet Med Assoc. 2008;233(1):122–128.

5.  Clendaniel DC, Sivacolundhu RK, Sorenmo KU, et al. Association between macroscopic appearance of liver lesions and liver histology in dogs with splenic hemangiosarcoma: 79 cases (2004–2009). J Am Anim Hosp Assoc. 2014;50(4):e6–e10.

6.  Tripp CD, Fidel J, Anderson CL, et al. Tolerability of metronomic administration of lomustine in dogs with cancer. J Vet Intern Med. 2011;25(2):278–284.

7.  de la Riva GT, Hart BL, Farver TB, et al. Neutering dogs: effects on joint disorders and cancers in golden retrievers. PLoS One. 2013;8(2):e55937.

  

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Kim A. Selting, DVM, MS, DACVIM (Oncology), DACVR (Radiation Oncology)
College of Veterinary Medicine
University of Missouri
Columbia, MO, USA


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