Canine Hemangiosarcoma: Is There A Light At The End of Tunnel
Hope Veterinary Specialists
40 Three Tun Road
Malvern, PA 19355 USA
Cliffdoc2000@yahoo.com
Introduction
Hemangiosarcoma is a highly malignant tumor of endothelial cells, hemangiosarcoma (HSA) is
diagnosed more frequently in dogs than in any other domestic species, and is associated with a high
fatality rate. 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.
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 a
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 nonendothelial, 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, 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 histopathologyand 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.
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