Page 795 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

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Miscellaneous Tumors

SECTION A: HEMANGIOSARCOMA AS in murine and human studies 22–24 ; although it appears that
p53 and Ras mutations are infrequent in canine HSA, 25,26 PTEN
inactivation was demonstrated in more than 50% of evaluated
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CHRISTINE MULLIN AND CRAIG A. CLIFFORD canine HSA samples. Key growth- and apoptosis-regulating pro-
teins such as pRB, cyclin D1, Bcl2, and survivin are overexpressed
Incidence and Risk Factors in HSA when compared with hemangiomas or normal tissues. 26,28
There is growing evidence that dysregulation of angiogenic
Hemangiosarcoma (HSA), also known as malignant hemangio- pathways may be important in the pathogenesis of HSA. Several
endothelioma or angiosarcoma (AS), is a malignant tumor com- studies have demonstrated abundant expression of angiogenic
posed of neoplastic endothelial cells. HSA occurs more frequently markers such as vascular endothelial growth factor (VEGF), basic
in dogs than in any other species 1–4 and represents about 2% of fibroblast growth factor (bFGF), platelet-derived growth factor
all canine tumors in general and 45% to 51% of canine splenic (PDGF), and angiopoetin-2, with concomitant expression of their
malignancies. 1–5 HSA is much less common in the cat, occurring corresponding cellular receptors in HSA cells and tissues. 18,29–31
in approximately 0.5% of cats examined at necropsy and account- An increased level of VEGF was documented in the plasma of
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ing for 2% of all feline neoplasms in general. 6 dogs with HSA as compared with healthy controls, whereas
HSA is seen mostly in middle-aged to older animals, although serum endothelin-1, a proangiogenic vasoactive peptide, was
there are rare reports of HSA occurring in dogs less than 3 years of higher in dogs with splenic HSA as compared with healthy dogs
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age. 2,3,6,7 Any breed is potentially at risk, but German shepherds, and those with other splenic diseases. These findings suggest the
golden retrievers, Labrador retrievers, and other large-breed dogs are potential role for overstimulation of proangiogenic pathways as a
overrepresented in several case series. 2,3,6,8,9 There may be a slight male promoter of tumor cell proliferation and survival.
predisposition in dogs. 3,6,10 In cats, older domestic shorthairs are most
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commonly affected, although there is no clear sex predisposition. Pathology and Natural Behavior
In dogs, cutaneous HSA develops more frequently in the
skin along the ventral abdomen and conjunctiva in short-haired In the dog, the most common primary site for HSA is the
and lightly pigmented breeds, reflecting the causal association spleen. 1,3,5,6,8,34 Other frequent anatomic sites include the heart,
with ultraviolet light exposure that has also been documented in skin and subcutis, and liver. 3,12,15,35–39 Primary HSA has also been
research beagles. 12–14 Some reports suggest a hormonal association reported in the lung, kidney, retroperitoneal space, muscle, bone,
with canine HSA development, specifically with regard to neuter- oral and nasal cavities, eyelid and conjunctiva, urinary bladder,
ing, given the findings that HSA appears more common in spayed digit, and mediastinum. 7,40–48 Although HSA is the most common
females versus intact females and late neutered females versus intact splenic neoplasm encountered in the dog, it is by no means the
or early neutered females. 2,15,16 The significance of these findings only differential for splenomegaly or splenic masses in dogs 1,5,10,34
in the general population of client-owned dogs is unclear, because Two large pathologic studies reported that approximately 50% of
no large and well-controlled studies have been performed to assess dogs with splenic tumors had malignant disease and 50% to 74%
the effect of neutering on the risk of dogs developing HSA. of these malignancies were HSA, 1,34 whereas other studies evalu-
Although traditionally considered to develop from malignant ating dogs presenting with a nontraumatic hemoabdomen found
transformation of mature peripheral endothelial cells, recent that 63% to 70% of all dogs had HSA. 49–51 It is important to note
molecular data suggest that HSA may arise from bone marrow that several other splenic masses may have a similar gross and ultra-
progenitor cells that undergo dysregulated maturation and sub- sonographic appearance to HSA, and the differential diagnosis list
sequently move to peripheral vascular sites to form tumors. 17–19 for a dog with a splenic tumor includes other neoplasms (e.g.,
Furthermore, genomic profiling studies have identified distinct lymphoma, nonangiomatous/nonlymphomatous sarcomas) and
molecular subtypes of HSA that suggest a probable heterogeneity nonneoplastic etiologies (e.g., nodular hyperplasia, extramedullary
within this tumor type. 19–21 Mutations in tumor suppressor genes hematopoiesis, hematoma). 1,5,34 Interestingly, in one study larger
such as p53 and Ras have been implicated in the pathogenesis of splenic masses and heavier spleens were more likely to be benign. 52

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