By Type By Location
By Type By Location

Hemangiosarcoma

Content Author: Dr. Tristram Bennett, BVSc, MANZCVS, DACVS-SA

+ Signalment and Clinical Signs

Hemangiosarcoma (HSA) is more often seen in middle-aged to older animals and is far more common in dogs than cats.1-3 HSA can affect any breed, however large breed dogs are more commonly reported, in particular golden retrievers, German shepherds, poodles, and Labrador retrievers.1-4 A male predisposition has been reported inconsistently in the literature.2,3 There is some evidence that HSA is more common in spayed-female dogs than intact females.4 Further evidence suggests that neutered male and female dogs may be at increased risk of splenic HSA specifically.5 Domestic shorthair cats are the mostly commonly reported feline breed, however this may be due an over-representation of this breed in the veterinary population.6

Clinical signs depend on the location and stage of the tumor. Primary sites reported for HSA include skin (especially in sparsely haired regions of non-pigmented skin in associated with ultraviolet light induced neoplastic change)7,8, subcutis, muscle, bone, conjunctiva, cornea, retroperitoneal space, spleen, kidney, liver, ureter, urinary bladder, colon, falciform fat, heart, lung, mediastinum, brain, lymph node, tongue, oral cavity, and nasal cavity.1-3,7-30 The gross appearance of an HSA lesion is generally a raised, purple, grey, or dark red, soft, friable lesion that readily bleeds reflecting their vascular nature

Splenic HSA is one of the most commonly reported primary sites for this tumor.31,32 For patients with visceral HSA, spontaneous hemorrhage is frequently present at diagnosis with many patients presenting with hemorrhagic cavitary effusion and associated clinical signs of cardiovascular instability due to significant blood loss.33 Dogs presenting with spontaneous hemoperitoneum and a splenic mass have a greater likelihood of diagnosis of malignancy, particularly HSA, compared to those without hemoperitoneum.33-37 This may not hold true for small breed dogs presenting with splenic masses and hemoperitoneum.38 In fact small breed dogs with splenic masses may be less likely to have malignant lesions compared to large breed dogs and malignant lesions may be less likely to be HSA.39,40 One study showed an inverse relationship between splenic mass and a diagnosis of malignancy in that dogs with larger masses relative to splenic size or relative to body-weight were more likely to be benign.41

Dogs with cardiac HSA may present with cardiac tamponade associated with accumulation of hemorrhagic effusion within the pericardial space.14,15 Cardiac HSA lesions are most often reported in the right auricle or atrium though other sites have been reported including the ventricular wall, interventricular septum, and pericardium.42-44 Cardiac HSA may occur synchronously with splenic HSA, though this is perhaps less common than previously thought. A study (Boston et al 2011) found concurrent right atrial lesions of 8.7% of dogs with splenic HSA, compared with 25% of dogs having concurrent lesions in a previous publication (Waters et al 1988).45,46

Tumor biology of HSA varies with location. For example, cutaneous HSA (and possibly lingual and falciform HSA) typically has a less aggressive behavior compared with intramuscular and visceral forms with the latter being associated with rapid progression and early metastasis.7,25,27,47 Metastatic disease may develop hematogenously or via direct implantation within a body cavity with common sites of spread being the peritoneum, omentum, liver, lungs, and brain.1,4,48

+ Diagnosis

When HSA is suspected complete and thorough staging for metastasis is indicated. This includes hematology, serum biochemistry, coagulation profiles and thoracic, abdominal, cardiac, and potentially cranial imaging. Appropriate imaging modalities include three-view thoracic radiography, abdominal ultrasonography, thoracic and abdominal CT, echocardiography, CT or MRI of the head and scintigraphy/positron emission imaging.49-52 Contrast-enhanced CT, Triple-phase CT and CT texture analysis may be useful in differentiating splenic hemangiosarcoma from other splenic lesions though further investigation is necessary to validate these modalities for this purpose.53-55 Similarly contrast enhanced ultrasonography techniques have shown some merit in distinguishing benign and malignant splenic lesions.56,57

Hematologic findings may include anemia, schistocytosis, acanthocytosis, nucleated erythrocytes, thrombocytopenia, and neutrophilic leukocytosis. Altered coagulation is a common finding in patients presenting with visceral HSA.58,59 Serum biochemical changes are non-specific and generally reflect the systemic effects of the tumor though may also be related to the organs involved (such as elevated serum liver enzyme activity with hepatic lesions).60

The current TNM staging system for canine hemangiosarcoma is detailed in Table 1.

TNM Staging for Canine Hemangiosarcoma

T0 No evidence of tumor

T1 Tumor confined to primary site and/or dermis and < 5cm

T2 Tumor ruptured, invading subcutaneous tissues and/or >5 cm diameter

T3 Any T1 or T2 with tumor invading adjacent structures and/or muscle

N0 No evidence of regional lymph node involvement

N1 Regional lymph node involvement

N2 Distant lymph node involvement

M0 No evidence of distant metastasis

M1 Distant metastasis

Stage I T0 or T1, N0, M0

Stage II T1 or T2, N0 or N1

Stage III T2 or T3, N0 or N1 or N2, M1

Definitive diagnosis requires histologic sampling. Cytology of HSA lesions and effusions can be useful, though may be poorly sensitive due to hemodilution and possibly poor exfoliation of neoplastic cells.61-63 Additionally, there is risk of hemorrhage following fine needle aspiration. Histology can also lack sensitivity for splenic HSA, as a proportion of dogs histologically diagnosed with benign splenic masses have been reported to later develop metastatic disease.64 Biopsy of other gross pathology detected at the time of excision of the primary tumor is recommended as it may represent metastatic disease. This is especially true of concomitant hepatic lesions.65 Immunohistochemical staining for von Willebrand’s factor or CD31 can help to rule out other potential differentials and improve the confidence in a histologic diagnosis of HSA.66,67

Other potentially useful diagnostic tests for HSA include biomarkers such as serum thymidine kinase, collagen XXVII, plasma cardiac troponin I, vascular endothelial growth factor (VEGF) and urine basic fibroblast growth factor (bFGF) concentrations.68-72 Plasma cardiac troponin I has been showed to be significantly elevated in dogs with cardiac HSA.70

+ treatment

Surgery is indicated for excision of localized HSA lesions and for palliating actively bleeding primary or metastatic lesions. Where possible wide excision of cutaneous, subcutaneous, and muscular HSA is recommended, this may include limb amputation in some cases (such as intramuscular HSA). For splenic HSA complete splenectomy is the treatment of choice with concurrent meticulous exploration of the abdominal cavity for additional pathology. If additional intra-abdominal pathology is noted, it should not be assumed to represent metastatic disease and should always be confirmed cytologically or histologically. A study by Clendaniel et al found that only 50% of dogs with splenic HSA and grossly abnormal livers had metastasis on histology.65 Excision of right atrial appendage and right atrial HSA lesions and palliative pericardiectomy can be considered in appropriate cases.73,74

Chemotherapy is generally indicated for HSA other than in small non-metastatic dermal lesions amenable to complete excision. Doxorubicin containing protocols are typically considered most effective.75-78 Anti-angiogenic therapy and metronomic chemotherapy and thalidomide have also been proposed to have potential benefits.79-83

Radiation therapy (RT) is used on occasion in specific circumstances where HSA lesions are not amenable to excision. However due to the typically wide-spread nature of metastatic lesions and their dose limiting visceral locations the potential benefits of RT are often not able realized.84,85

There is some evidence that immunotherapy strategies may have some effect. There has been a report of doxorubicin used alongside a novel HSA vaccine prepared with lysates of allogenic canine HSA cell lines in dogs with various stages of disease. Humoral responses to the vaccine with minimal adverse effects were noted but a survival benefit remains unclear.86 Additionally, liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE), has been shown to have potential antimetastatic effects in a study of 32 dogs with splenic HSA, in the absence of gross metastases, treated with surgery and systemic chemotherapy. Dogs receiving L-MTP-PE had significantly longer disease-free and overall survival times compared to placebo control dogs. The L-MTP-PE dogs also had greater TNF-alpha and interleukin-6 serum concentrations compared to control dogs.87

Recent publications investigating ligand-targeted toxins against canine hemangiosarcoma, specifically EGFR-targeted bispecific angiotoxin (eBAT), have shown some therapeutic benefit with a good safety profile. When used alongside single agent doxorubicin chemotherapy in splenectomized dogs with HSA 6-month survival time was improved from <40% data-preserve-html-node="true" to approximately 70% with a number of dogs experiencing survival greater than one year.88,89 Further research is required to better understand optimal dosing protocol and to determine if there is a robust clinical benefit to this therapy.90 There exists limited published evidence of therapies for canine HSA in the field of alternative medicine. Anecdotal reports of beneficial effects of Yunnan Baiyao (YB) have been made. There is also some limited in vitro evidence of cytotoxic effects of YB on canine HSA cell lines.91 The effects of YB on coagulation parameters in patients with HSA have yet to be validated.92,93 A retrospective study investigating YB and epsilon-aminocaproic acid used in combination for presumed cardiac HSA in canine patients failed to show any clinical benefit.94 A study using single agent polysaccharopeptide in dogs with splenic HSA showed delayed metastasis and improved survival times, however the case numbers were very small and only comparison to historical controls was made.95

+ Prognosis

The prognosis for HSA varies widely depending on the location of the primary tumor, the stage of disease and therapy employed. The prognosis for dermal, non-metastatic HSA is generally excellent with surgery alone affording long-term control of disease in both dogs and cats.6,47,96,97 Due to the wide-spread pre-neoplastic change to skin damaged by ultraviolet radiation, additional development of de novo lesions is common.47 Median survival times (MSTs) for patients with HSA confined to the dermis treated with only surgery are reported to be 780-987 days. Those patients with ventrally located dermal HSA, and with associated solar-induced dermal pathology, may have a more favorable prognosis (MSTs of 1085 and 1549 days respectively).47 In patients where disease extends beyond the dermis the prognosis is guarded to poor with a higher risk of metastatic disease developing.8,47,98,99 For HSA arising from a subcutaneous or intramuscular location the prognosis is also guarded, and adjuvant chemotherapy is generally recommended. The reported prognosis for subcutaneous HSA varies widely (MST of 8 months to >3years) when treated with surgical excision, doxorubicin-based chemotherapy and/or radiation therapy.8,99 This may be due to the stage of the disease at the time of treatment. The MST for intramuscular HSA treated similarly is reported to be approximately 8-9 months.8,99 Due to the highly metastatic nature of visceral HSA the prognosis for dogs treated with surgery and no adjuvant therapy is poor with median survival times of 19 to 86 days reported.1,4 The addition of doxorubicin chemotherapy protocols to treatment protocols extends median survival times to 172-250 days, though only approximately 10% of patients survive beyond a year.75-77 Primary cardiac and retroperitoneal HSA has a particularly poor prognosis with median survival times of 42-175 and 37.5 days reported respectively.26,14,74 Lingual HSA has been found to a have a somewhat better prognosis compared to visceral locations with one case series of 20 dogs reporting a median survival time of 553 days following surgical removal. All lesions were low to intermediate grade on histology and no survival advantage of adjuvant chemotherapy was found.25 Likewise primary HSA of the falciform fat and kidney may have a better prognosis than other visceral locations. A small case series of dogs with primary HSA of the falciform fat reported an MST of 339 days.25 In a series of 14 dogs with primary renal HSA an overall MST of 278 days was found, however dogs presenting with hemoperitoneum had significantly shorter survival (62 days versus 286 days).100 Other potential prognostic factors in canine HSA include tumor stage and grade. Dogs with stage I splenic HSA have reported MSTs of 239-355 days comparted to 120-148 days for dogs with stage II disease when treated with surgery and adjuvant chemotherapy.87,101 Though this has not been shown consistently across all studies.102 There is some evidence that histologic criteria such as mitotic count, cellular differentiation, nuclear atypia, and grading may be predictive of prognosis with respect to survival.75 As in dogs the prognosis for visceral HSA in cats is also poor, with greater than three-quarters of patients having metastatic disease at the time of diagnosis.103 The MST for feline visceral HSA has been reported to range from 77-197 days with death generally attributed to metastatic disease.103,104 The prognosis for feline dermal and subcutaneous HSA can be favourable with MSTs of 283 to 912 days.6,97 Subcutaneous HSAs are associated with a greater risk of incomplete excision and local recurrence compared to their dermal counterparts, however.6 Mitotic count has also been associated with prognosis in feline HSA, with shorter survival times documented in lesions with > 3 mitotic figures in 10 hpfs.6

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