Canine Hemangiosarcoma: Is There A Light At The End of Tunnel

Introduction

Hemangiosarcoma (HSA) is a highly malignant tumor of endothelial cells and is diagnosed more frequently in dogs than in any other domestic species. 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. While dogs of any breed can develop HSA, German shepherds, Golden retrievers appear predisposed. 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. (Figure 1)

The definitive cause of canine HSA remains uncertain, though the strong breed association suggests heritable factors are present to explain this genetic predisposition and, in fact, gene expression phenotypes were shown to vary between HSA cells from different breeds in a recent study. It has been identified that HSA originates for circulating endothelial precursors and not from mature endothelial cells within an organ.

With the advent of platforms enabling evaluation of genome wide gene expression, we are beginning to identify genes associated with HSA. Differences between HSA cells and non-malignant endothelial cells in regards to increased expression of genes involved in inflammation, angiogenesis, adhesion, invasion, metabolism, cell cycle, signaling, and patterning have been documented. Importantly, this “signature” reflected not only a cancer-associated angiogenic phenotype, but could distinguish HSA from other non-endothelial, angiogenic bone marrow-derived tumors such as lymphoma, leukemia, and osteosarcoma. Specific abnormalities in oncogenes (genes that promote growth), and tumor suppressor genes (genes that retard growth) have been identified, all of which play a role in tumor formation. More specifically may cancer“driver” genes and their associated signal pathways have been identified with HSA.

Clinical 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 sufficiently stable. Complete clinical staging should ideally include three-view high-detail thoracic radiographs (Figure 2), abdominal ultrasonographic study, and echocardiography, in addition to standard bloodwork. In select cases, additional imaging techniques (computed tomography or magnetic resonance imaging).  Studies of splenic and hepatic lesions have shown that MRI and CT carry a high sensitivity and specificity in determining benign from malignant processes. Furthermore, the increased sensitivity of thoracic CT for early pulmonary metastasis detection has been reported. With the increasing use of such diagnostic techniques in veterinary medicine, they are gradually incorporated in the thorough staging of dogs with HSA.

The definitive diagnosis of HSA is obtained with histopathology and this generally obtain via surgery. A few studies evaluating dogs with nontraumatic hemoabdomens noted that 65-70% were diagnosed with HSA. Interestingly, a recent study evaluating 65 dogs that underwent splenectomy, including 30 dogs (46%) with HSA, documented larger splenic masses, or higher mass-to-splenic volume ratio, and heavier spleens (as a % of body weight) were more likely to be benign. The development of noninvasive biomarkers with specificity to HSA would be clinically useful for not only early detection and treatment but also to monitor for progression of disease. Several recent studies have evaluated such markers in both the blood and effusion of dogs with HSA. For cardiac HSA, cardiac troponin I (cTnI) has proven to be a highly specific and sensitive marker for myocardial cellular damage in many mammalian species. A recent study noted a specific plasma cTnI concentration (> 0.25 ng/mL) could identify cardiac involvement in dogs with HSA at any site (sensitivity, 78%; specificity, 71 %), and could identify HSA in dogs with pericardial effusion (sensitivity, 81%; specificity, 100%). Evaluation of a fragment of collagen XXVII noted high concentrations in serum of dogs diagnosed with advanced stage HSA. Thymidine kinase (TK) is a cytosolic enzyme whose activity is closely correlated with the DNA synthesis and its expression is generally restricted to proliferating cells. Serum TK1 activity was significantly higher in dogs with HSA than in normal dogs. Even though a prospective evaluation of TK1 in 62 dogs with hemoabdomen due to benign splenic masses or HSA was unable to distinguish between the two, the ability to discriminate between the two became significant when a specific two tiered cut off system was implemented, making TK1 an attractive biomarker.

Therapy

Traditional therapy for HSA, as for other cancers, involves surgery, radiation therapy, and systemic cytotoxic chemotherapy, alone or in a multimodality setting.

Surgery – Splenectomy, liver lobectomy, excision of a dermal or resectable subcutaneous nodule, and right auriculectomy have all been reported. Such surgeries are performed to remove all macroscopic tumor tissue, and prevent further risk of acute hemorrhage, development of disseminated intravascular coagulation, or death. Surgery alone for splenic, cardiac, subcutaneous/intramuscular, or hepatic HSA is generally considered purely palliative, with median survival times (MST) typically averaging 1-3 months with splenectomy alone.

Conventional chemotherapy – Doxorubicin (DOX)-based adjuvant chemotherapy, with or without the addition of cyclophosphamide or vincristine is considered “standard of care”. Common protocols include single agent DOX, DOX and cyclophosphamide (AC protocol), and vincristine, DOX and cyclophosphamide (VAC protocol). Survival times ranging from 140 to 202 days have been reported for the various doxorubicin-based protocols, however, no protocol is regarded as clearly superior. Although, small numbers (n=9 and HSA of several locations), a recent study evaluating Adriamycin and Dacarbazine (DTIC) noted a median survival >550 days for dogs post surgical resection.

Conventional chemotherapy also has been evaluated with macroscopic HSA. In 18 dogs with inoperable subcutaneous HSA treated with DOX monotherapy, the overall response rate was 38.8% using World Health Organization (WHO) criteria, 38.8% using Response Evaluation Criteria in Solid Tumors (RECIST) criteria and 44% using tumor volume criteria, for an overall median response duration of 53 days (range 13-190 days). An aggressive protocol combining dacarbazine, DOX and vincristine (DAV protocol) was evaluated in 24 dogs with advanced-stage inoperable HSA and showed a response rate approaching 50%, including five complete and four partial responses, for a median time to tumor progression or 101 days and a reported MST of 125 days.

Radiation therapy – A study of 20 dogs with measurable, histologically-confirmed nonsplenic HSA treated with palliative radiation therapy showed subjective reduction in tumor size in 14 dogs (70%), with 4 complete responses and a MST of 95 days. In such cases, palliation is obtained by decreasing pain and bruising, in addition to tumor shrinkage, and will generally be combined with systemic doxorubicin-based chemotherapy.

Novel Therapy

Since the combination of traditional therapeutic modalities has reached a plateau unlikely to be surpassed, with median survival times averaging 6-7 months, new therapies are impatiently awaited. The growing body of knowledge on the molecular alterations observed in canine HSA cells may hopefully unveil numerous novel targets. Antiangiogenic therapy in the form of tyrosine kinase inhibitors designed to block aberrant signal pathways in HSA have shown promise in vitro. A recent study evaluating Toceranib (Palladia; Zoetis) in dogs with splenic HSA following surgery and standard doxorubicin therapy noted no significant improvement in overall survival. The use of traditional chemotherapy agents is being revisited through novel methods or schedules of administration. A pilot study evaluating inhalational therapy with DOX and paclitaxel demonstrated encouraging results on canine patients with pulmonary metastasis from HSA. The daily administration of low doses (metronomic dosing) of traditional cytotoxic chemotherapy agents is another new approach. The therapeutic target is then shifted from the cancer cells to the endothelial cells by administering frequent low doses of chemotherapy. By so doing, the common problems of toxicities and drug resistance can be largely avoided. A small pilot study evaluated a continuous low-dose protocol of cyclophosphamide, piroxicam and etoposide in 9 dogs with stage II splenic HSA in the adjuvant setting. When comparing their median survival time to that of historical controls treated with DOX, no difference was observed. Two recent studies have documented responses of HSA in the macroscopic disease setting to continuous low-dose administration of CCNU (lomustine) and chlorambucil. The authors have recently completed a large study evaluating the addition of a metronomic protocol to standard doxorubicin.

Alternative medicine:

Polysaccharopeptide (PSP), the bioactive agent of the mushroom Coriolus versicolor

(aka Cloud mushroom, turkey tail, or Yunzhi mushroom) was evaluated in a small study of 15 dogs receiving three dosings. In the patients receiving the high dose (n=5), a median survival of 112 days was noted. A current three arm study evaluating doxorubicin alone, doxorubicin + PSP (I’m Yunity) or PSP alone is ongoing. Yunnan Baiyao is a hemostatic powdered alternative medicine used anecdotally to decrease hemorrhage. The company website mentions that the steroid progesterone is in the formula, in addition to several saponins, alkaloids and calcium phosphate. In vitro data exists with canine HAS cell lines, however, no in vivo studies exist.

Summary:

Canine HSA remains an aggressive, highly metastatic cancer, and the survival times obtained with traditional therapy have not been surpassed in recent years. Hope for improved prognosis in the near future remains, and is based on ongoing research promising mainly earlier diagnosis and successful novel targeted therapies.

Submitted by Craig A Clifford DVM, MS, DACVIM (Oncology)

References:

Tamburini BA, Trapp S, Phang TL, et al. Gene Expression Profiles of Sporadic Canine Hemangiosarcoma Are Uniquely Associated with Breed. Plos One 2009; DOI: 10.1371/journal.pone.0005549.

Gorden BH, Kim JH, Sarver AL, et al. Identification of Three Molecular and Functional Subtypes in Canine Hemangiosarcoma through Gene Expression Profiling and Progenitor Cell Characterization The American Journal of Pathology 2014;184:985–995.

Dickerson EB, Marley K, Edris W, et al. Imatinib and Dasatinib Inhibit Hemangiosarcoma and Implicate PDGFR-β and Src in Tumor Growth. Translational Oncology 20136:158–168.

Finotello R, Stefanello D, Zini E, et al. Comparison of doxorubicin–cyclophosphamide with doxorubicin–dacarbazine for the adjuvant treatment of canine hemangiosarcoma. Veterinary and Comparative Oncology

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).  Journal of the American Animal Hospital Association 50.4 2014: e6-e10.

Wirth KA, Kow K, Salute ME, et al. “In vitro effects of Yunnan Baiyao on canine hemangiosarcoma cell lines.” Veterinary and Comparative oncology 2014; DOI: 10.1111/vco.12100

Kahn SA, Mullin CM, de Lorimier LP, et al. Doxorubicin and deracoxib adjuvant therapy for canine splenic hemangiosarcoma: a pilot study. The Canadian Veterinary Journal 2013;54:237-242.

Mullin CM, Arkans MA., Sammarco CD, et al. Doxorubicin chemotherapy for presumptive cardiac hemangiosarcoma in dogs. Veterinary and Comparative oncology. 2014 DOI: 10.1111/vco.12131.

Figure 1. Splenic hemangiosarcoma. Note the multilobulated nature of the tumor. Photo courtesy of JuliusLiptak, BVSc, MVetLinStud, FACVSc, DACVS, DECVS.

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Figure 2. Three-view thoracic radiographs from a 12 year old spayed female Labrador retriever.  Numerous poorly to well defined small soft tissue nodules are present throughout the lungs consistent with metastatic hemangiosarcoma. Images and description courtesy of Chris Ryan, VMD, DABVP, DACVR.

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