Received: 24 January 2020 Revised: 12 February 2021 Accepted: 4 May 2021

DOI: 10.1002/vetr.585

REVIEW

Canine and feline haemangiosarcoma

Maureen A. Griffin William T. N. Culp Robert B. Rebhun

School of Veterinary Medicine, University of Abstract

California-Davis, Davis, California, USA
Correspondence
William T. N. Culp, School of Veterinary
Medicine, University of California-Davis,
One Garrod-Drive, Davis, CA 95616, USA.
Email: wculp@ucdavis.edu
Introduction: Haemangiosarcoma (HSA) is a malignant neoplasm of dogs
and cats that is suspected to originate from a pluripotent bone marrow pro-
genitor with a complex and multifactorial pathogenesis.
Approach: Pertinent literature was identified, reviewed, and summarized for
inclusion in the manuscript.
Results/Interpretation: Dogs are more frequently diagnosed with HSA than
cats, and primary sites of this disease include dermal, subcutaneous/
intramuscular, and visceral (most commonly the spleen). Dogs and cats with
HSA generally have a poor prognosis owing to the rapid and widespread
metastasis typically associated with this disease. However, some forms such
as cutaneous HSA behave in a less aggressive fashion with improved out-
comes. Surgical excision and anthracycline-based chemotherapy remain the
mainstays of treatment, although novel treatment modalities are currently
under investigation for potential roles in treatment of this disease.
Conclusion: This review aims to describe the clinical presentation and pro-
gression of the various forms of HSA in dogs and cats as well as to provide a
systematic review of the veterinary literature with a focus on the various pub-
lished treatment options and associated outcomes.

INTRODUCTION compared to control dogs.8,9 Thus, the pathogenesis

Haemangiosarcoma (HSA), a malignant neoplasm
that resembles angiosarcoma in people, has histor-
ically been considered to originate from vascular
endothelium on the basis of histopathological find-
ings; however, there is growing evidence that these
tumours may originate from a pluripotent bone mar-
row progenitor.1–4 These bone marrow progenitor
cells appear to be near or at the stage of commit-
ment to an endothelial cell line (hemangioblasts to
angioblasts).3 These cells may either reside in the
vascular endothelium and subsequently undergo
neoplastic transformation or alternatively they may
migrate to sites of vasculature following neoplastic
transformation.3 In addition, as with many tumour
types, genetic mutations in oncogenes and tumour
suppressor genes may play a role in the develop-
ment of HSA. For example, mutations in tumour
suppressor genes such as p53, Ras, and phosphatase
and tensin homolog (deleted from chromosome 10)
have been detected in association with HSA in mul-
tiple species.5–7 Furthermore, abnormal regulation
of angiogenesis may play a role in the development
of HSA. For instance, plasma vascular endothelial
growth factor (VEGF) and serum endothelin-1 have
been detected at increased levels in dogs with HSA
of HSA appears to be multifactorial and complex.
Across species, dogs are diagnosed with HSA most
frequently, and this disease appears to be less com-
mon in cats and rare in people.10,11 In dogs, HSA com-
prises approximately 5% of all non-dermal primary
malignant tumours, less than 5% of all dermal tumours
and approximately 50% of all splenic tumours.11–15
The reported incidence of HSA in cats is less than 2%,
and HSA accounts for less than 0.1% of all human
neoplasia.1,16,17 HSA most commonly affects senior
animals, and there appears to be a slight male pre-
disposition in dogs.18–20 German shepherd dogs are
among the most commonly reported dog breeds with
HSA, and HSA is the most common cause of neoplasia-
associated death in Golden Retrievers, although any
breed of dog or cat can acquire this disease.18,21–24
In cats, domestic shorthairs appear to be most com-
monly affected with HSA, and there is no known sex
predilection in this species.25
Given the high prevalence of this disease in dogs
and the relatively poor prognosis for visceral HSA,
many studies characterizing the disease and a mul-
titude of treatment options have been published for
dogs, whereas much of this information is lacking
in cats. This manuscript aims to describe the clini-
cal presentation and progression of the various forms

Vet Rec. 2021;e585. wileyonlinelibrary.com/journal/vetr © 2021 British Veterinary Association 1 of 13

https://doi.org/10.1002/vetr.585
2 of 13
of HSA in dogs and cats as well as to provide a
review of the veterinary literature with a focus on the
various published treatment options and associated
outcomes.
DISCUSSION
Neoplastic behaviour
The most common primary location for HSA in dogs
is the spleen, although other common primary sites
include the right atrium, dermis and subcutaneous
tissue, and liver.10,18,19,21,26–31 HSA is the most com-
mon form of primary cardiac neoplasia in dogs,
and the most common sites of cardiac HSA are the
right atrium and right auricle.30–32 Less frequently
reported primary HSA sites in dogs include the kid-
ney, retroperitoneum, urinary bladder, uterus, lung,
left ventricle of the heart, region of the great ves-
sels, oral cavity and tongue, bone, spinal canal, mus-
cle, digit and cornea.18,26,33–43 In cats, the primary
site of HSA is typically either cutaneous/subcutaneous
or visceral (most commonly intra-abdominal tis-
sues such as liver, intestine, abdominal lymph node,
mesentery, spleen, omentum and pancreas, although
other reported sites include the diaphragm, lung,
thoracic cavity, nasal cavity, brain and ocular/peri-
ocular).17,25,44–48 Primary right atrial HSA has also
been documented in a cat.49 Rare occurrences of
HSA secondary to foreign material (such as steel sta-
ples and polypropylene suture) have also been docu-
mented in cats.50,51
At the time of initial evaluation, HSA may be solitary,
multifocally distributed within an organ or widely dis-
seminated with metastasis. The typical gross appear-
ance of HSA is non-encapsulated and poorly cir-
cumscribed, and friability can lead to complications
associated with tumour rupture and spontaneous
haemorrhage.11 In general, HSA is an aggressive neo-
plasm in dogs that exhibits rapid and wide-spread
metastasis, which may be attributed to its vascular
association.18,23,52,53 However, dermal HSA without
invasion into the subcutaneous tissues may be an
exception to this finding, as these tumours typically
behave in a less systemically aggressive fashion.29
Among these non-visceral HSA sites, dogs with der-
mal tumours that are invasive into the subcutaneous
tissue and non-solar induced dermal HSA appear to
be at increased risk for metastasis and have decreased
survival times as compared to dogs with non-invasive
and solar-induced dermal HSA.54
Metastasis of HSA typically occurs via haematoge-
nous routes or seeding throughout a body cavity (most
often the abdomen) following tumour rupture.11 The
most commonly documented sites of HSA metastatic
disease include the liver, omentum, mesentery and
lungs.18,55 Other documented sites of metastasis
include the peritoneum, kidney, adrenal gland, lymph
nodes, diaphragm and muscle.11,18,55 In dogs, HSA
appears to be the tumour that most commonly metas-
tasizes to the brain.56,57
Veterinary Record
HSA is often considered to be less aggressive in
cats than in dogs, although the visceral and cutaneous
forms of disease in this species generally have sub-
stantially different neoplastic behaviours.11 Visceral
HSA in cats appears to have an aggressive biologic
behaviour with a high rate of metastatic and multi-
focal disease (similar to dogs), with common sites of
metastasis including the liver, diaphragm, omentum,
pancreas and lung.19,25,45,48 In contrast, dermal and
subcutaneous HSA in cats is typically associated with
a relatively low rate of metastatic disease and high
degree of local invasion; however, it is important to
note that there appears to be a smaller population of
cats with more systemically aggressive forms of this
disease.25,58–60
One-third to two-thirds of all dogs with splenic
lesions reportedly have malignant disease, with
HSA comprising the majority of the malignant
diagnoses.11,15,18,20,61,62 Therefore, in dogs with
splenic masses, HSA should remain the highest dif-
ferential. However, one recent retrospective study on
dogs with splenic masses revealed that genotype-
based breed group had predictive value for malignant
splenic disease and specifically HSA.63 In this study,
the genotype group containing German shepherd
dogs had a significantly greater proportion of HSA
diagnoses compared to all other genotype groups,
and membership in this genotype-group was asso-
ciated with a 75% positive predictive value of HSA.63
Alternatively, the groups containing spaniels, poodles,
mastiffs, bulldogs and terriers had the lowest inci-
dence of HSA.63 Therefore, breed should be taken into
account in the consideration of potential HSA in dogs
that present with a splenic mass.
Multiple studies have found a greater incidence (up
to 70%) of HSA in dogs with splenic masses that
present with haemoperitoneum as compared to dogs
with splenic masses without haemoperitoneum.63–66
A recent study on spontaneous haemoperitoneum in
dogs suggested that this risk for splenic HSA may
also be related to dog size.67 In this study, small
dogs (≤20 kg) were less likely to have a splenic source
and more likely to have a hepatic source of haemor-
rhage as compared to large dogs (>20 kg), and small
dogs were more likely to have diseases other than
splenic HSA as the cause of haemoperitoneum as com-
pared to large dogs.67 One study on cats with sponta-
neous haemoperitoneum reported a neoplastic source
in 46% and a non-neoplastic source in 54%; of the
cats with neoplastic disease, HSA was the most com-
mon malignancy, and the spleen was the most com-
mon site/source of haemorrhage.68
For the subset of dogs with incidentally detected,
non-ruptured splenic masses or nodules (relative to
dogs with splenic masses and haemoperitoneum),
the prognosis appears to be relatively improved, as
one study revealed a histopathologic diagnosis of
benign disease following splenectomy in the majority
of these patients (74/105, 70.5%).69 However, for dogs
with non-ruptured splenic masses or nodules that
had a diagnosis of malignant disease, HSA remained
the most common form of malignant disease (18/31,
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58%).63,69 Another study evaluated the role of size of
the splenic mass as a potential risk factor for malignant
disease.70 For 65 dogs that underwent splenectomy for
a splenic mass, dogs with benign splenic masses had
a significantly greater mean mass-to-splenic volume
ratio and mean splenic weight as a percentage of body
weight compared to dogs with HSA.70 Therefore, large
splenic mass size may not be indicative of malignant
disease.
There is also a well-documented association of con-
current right atrial and splenic HSA in dogs, and this
association has been reported to occur in up to 25%
of dogs with splenic HSA.55 A more recent study doc-
umented a concurrent right atrial mass in 8.7% of
dogs presenting for splenic HSA, whereas a concur-
rent splenic mass was documented in 29% of dogs pre-
senting for right atrial HSA.71 Therefore, the incidence
of this association between cardiac and splenic HSA
appears to be influenced by whether signs at presen-
tation are associated with a cardiac or splenic mass.
History and clinical signs
Visceral (non-cardiac) HSA
Presenting complaints for dogs and cats with HSA
vary and depend on the primary tumour location and
extent, possible tumour rupture and haemorrhage and
potential metastatic disease. Signs can be vague and
non-specific (such as lethargy, inappetence, weight
loss and vomiting) or severe and life-threatening (such
as acute collapse and cardiopulmonary arrest).71,72
A common presenting complaint for visceral HSA in
dogs and cats involves acute weakness or collapse sec-
ondary to anaemia and hypovolaemia; however, clini-
cal signs may be present for a prolonged period of time
or may wax and wane in nature.11,48,65,66,68,73 In these
cases, it is theorized that rupture of the visceral HSA
results in anaemia, hypovolaemia, and clinical signs of
weakness and collapse with subsequent stabilization
due to reabsorption of the peritoneal red blood cells,
clot formation and cessation of haemorrhage.
Possible physical examination findings in dogs and
cats with visceral HSA include a palpable abdomi-
nal mass, signs of anaemia/hypovolaemic shock (e.g.,
pale mucous membranes, prolonged capillary refill
time, tachycardia, poor pulse quality, cool extrem-
ities, obtundation) and abdominal distention/fluid
wave.48,66,72 Arrhythmias can also be detected in
patients with splenic HSA.74,75 Possible causes of
arrhythmias in dogs with splenic masses include
myocardial hypoxia due to anaemia or hypovolaemia,
myocardial metastasis and localized or systemic cate-
cholamine release.74
Cardiac HSA
For dogs with cardiac HSA, additional signs associ-
ated with pericardial tamponade and right-sided heart
failure may occur.11,71,72 On physical examination,
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patients with cardiac HSA and pericardial tampon-
ade may have muffled heart and lung sounds, pulsus
parodoxus and signs of right-sided heart failure.71,72
Arrhythmias can also be detected in patients with car-
diac HSA.75
Dermal/subcutaneous HSA
For dogs and cats with non-visceral HSA, presenting
complaints commonly include the presence of dermal
or subcutaneous mass lesions (often in predisposed
dog breeds with minimal pigmentation and thin hair
coats).54 For patients with cutaneous/subcutaneous
HSA, tumours may be solitary or multifocal, with
lesions most often occurring on the ventrum in dogs
and cats.29,54,59 Dermal HSA lesions can typically be
characterized as firm, raised, dark red/purple papules
or nodules, whereas those that involve the subcuta-
neous tissues may be firm or soft with a common
dark red/purple colouration.29 Dermal ulceration is
also a common finding in patients with cutaneous
HSA.29
Diagnosis and systemic evaluation
Overview
Definitive diagnosis of HSA typically requires biopsy
and histopathology. Fine-needle aspiration and cytol-
ogy are generally considered to be of low diag-
nostic utility due to haemodilution associated with
sampling.76 For cutaneous or subcutaneous lesions in
dogs and cats, needle-core biopsies can be performed
to obtain a diagnosis; however, this should be avoided
for visceral tumours due to the risk of haemorrhage
and seeding of the peritoneum.11 Due to the cavitary
nature of HSA, histopathologic differentiation of HSA,
haemangioma, and haematoma can be challenging,
and large samples of the mass are needed to improve
diagnostic ability to confirm the presence of HSA.77,78
If histologic features of HSA including immature,
pleomorphic endothelial cells are not readily appar-
ent, immunohistochemistry for von Willebrand’s fac-
tor, CD31/platelet endothelial cell-adhesion molecule,
claudin-5, CD117 and VEGF can be useful markers to
aid in the diagnosis of HSA.20,58,79–84 However, it is
advised to maintain an index of suspicion for malig-
nant disease even in dogs that have a histopathologic
diagnosis of benign disease (such as haemangioma
or haematoma) given the difficulty in differentiating
these tumour types and the significant difference in
prognosis between them. One study that evaluated
long-term outcomes in dogs with a histopathologic
diagnosis of splenic haematoma following splenec-
tomy documented development of metastatic dis-
ease in four of 35 (11%) dogs, thereby suggesting
inaccurate initial diagnosis as a benign lesion.77 For
patients with cutaneous HSA, a solar-induced com-
ponent can be histologically determined by the pres-
ence of solar elastosis, ischaemic change of collagen,
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TA B L E 1 Clinical staging system for HSA in dogs11
Primary tumour (T)
T0: No gross tumour
T1: Tumour < 5 cm diameter and contained within one tissue
type
T2: Tumour > 5 cm diameter or ruptured or invasive into
subcutaneous tissue
T3: Tumour invasive into adjacent structures (such as muscle)
Clinical stage
I T0-1, N0, M0
II
III
dermatitis, superficial dermal fibrosis and epidermal
dysplasia.54
Thorough staging is important in patients with HSA
to assess for location and extent of the primary tumour
as well as locoregional and distant metastatic dis-
ease. Routine diagnostics generally include labora-
tory diagnostic testing (complete blood count and
serum biochemistry panel), cytologic analysis of any
cavitary effusion (including packed cell volume and
total solids in comparison to peripheral blood), radio-
graphs and/or CT of the thorax, ultrasound and/or
CT of the abdomen and possible echocardiogram.
Coagulation testing can be performed to assess for
concurrent coagulopathy and to help guide treat-
ment recommendations. All diagnostic results should
be compiled for each patient, and a clinical stage
can subsequently be assigned. A three-tiered clinical
staging system (stage I-III) for canine patients with
HSA has been established and is based on primary
tumour extent, regional lymph node metastasis and
distant metastasis (Table 1).11 This staging system is
valuable in determining prognosis and guiding treat-
ment options and recommendations. A clinical stag-
ing system for this disease in cats has not yet been
documented.
Several biomarkers have also been evaluated in
patients with HSA. Plasma cardiac troponin I concen-
tration testing may also be a valuable diagnostic tool
for dogs with cardiac HSA, as the median plasma car-
diac troponin I concentration has been suggested to
be greater in dogs with cardiac HSA than both dogs
with pericardial effusion not caused by HSA and dogs
with non-cardiac HSA.85 Thymidine kinase 1 and col-
lagen XXVII peptide are two other biomarkers that may
have a role in diagnosis and monitoring of HSA.86,87
Use of biomarkers in the diagnosis and staging of HSA
in dogs and cats is still being evaluated and is not yet
used frequently in clinical patients.
Laboratory and clinical pathological
testing
Complete blood count findings in dogs and cats with
HSA often include anaemia (regenerative or non-
Veterinary Record
Lymph nodes (N) Distant metastasis (M)
N0: No evidence of regional lymph M0: No evidence of distant
node metastasis metastatic disease
N1: Regional lymph node metastasis M1: Distant metastatic disease
N2: Distant lymph node metastasis
T1-2, N0-1, M0
T2-3, N0-2, M1
regenerative) with red blood cell morphology changes;
these findings may be secondary to haemorrhage,
decreased bone marrow production and haemolysis
due to microangiopathy.88–91 Importantly, however,
there has been no detected difference in erythrocyte
morphology abnormalities between dogs with HSA
and non-HSA-associated haemoperitoneum, and
these findings cannot be used reliably to assist in
differentiating benign and malignant disease.92 There
is also a potential association between immune-
mediated haemolytic anaemia and the presence
of HSA.93 Thrombocytopenia is another common
finding in patients with HSA; one study showed
thrombocytopenia in 75% of dogs with HSA.90 Throm-
bocytopenia may occur secondary to haemorrhage,
consumption, decreased production, increased
sequestration and intratumoral destruction.88,89
Neutrophilia can also be present due to a condi-
tion or tumour necrosis with inflammation.11,88 It
is also important to consider secondary coagulation
testing, as disseminated intravascular coagulation
has been diagnosed in approximately 50% of dogs
with visceral HSA.89,90,94 Criteria for disseminated
intravascular coagulopathy include thrombocy-
topenia, increased fibrinogen degradation products,
increased prothrombin and/or partial thromboplas-
tin time, fragmented red blood cells and decreased
fibrinogen.90 Serum biochemistry abnormalities in
patients with HSA are generally non-specific and
can include hypoproteinaemia, potentially due
to decreased production and mild secondary liver
enzyme elevations.48,64 Any peritoneal, pleural and
pericardial effusions should also be sampled for
analysis in dogs and cats with suspected HSA. These
effusions are typically haemorrhagic and non-clotting.
Cytology is rarely useful to obtain a diagnosis of HSA
due to significant haemodilution.11,95 However, these
samples are important in that comparison of effu-
sion, and peripheral packed cell volume can indicate
whether haemorrhage is active or inactive, which can
subsequently dictate treatments pursued. These effu-
sions can also be evaluated for VEGF concentrations,
as VEGF concentration has been assessed in effusions
(peritoneal, pleural, pericardial) as well as plasma of
dogs.8,96 One study found that dogs with HSA were
Veterinary Record
F I G U R E 1 A single ultrasound image of a
splenic mass. Multiple hypoechoic cavitations are
visible throughout the mass, which is deforming the
splenic capsule
more likely to have increased concentrations of VEGF
in plasma as compared to healthy dogs.8 Similarly,
the concentration of VEGF in effusion samples from
dogs has been characterized as significantly greater
than in normal canine plasma and even the plasma of
dogs with HSA.96 However, it is important to note that
no difference was found between VEGF concentra-
tions in effusions of dogs with malignant and benign
sources of the effusion.96 This diagnostic test is not
widely used in clinical patients, and more information
regarding its clinical utility in supporting a diagnosis
of HSA is needed.
Diagnostic imaging
Abdominal ultrasound (Figure 1) is recommended
over radiographs in patients with suspected HSA to
enable thorough evaluation of the abdomen for a pri-
mary tumour site (in cases of visceral HSA) as well
as possible peritoneal metastatic disease.11 Moreover,
peritoneal effusion may decrease serosal detail, and
therefore the sensitivity of detecting a visceral mass,
on radiographs. Visualization of splenic or hepatic
target lesions (nodules or masses with isoechoic or
hypoechoic centers and hypoechoic peripheries) have
been correlated with malignant disease.97 Ultrasono-
graphic findings alone, however, cannot rule in or
out a diagnosis of HSA. Although multifocal splenic
lesions of similar ultrasonographic appearance are
often consistent with malignant disease, and single
splenic lesions are commonly benign, malignant neo-
plasia such as HSA can manifest as focal cavitary
lesions on ultrasound as well.98 Contrast-enhanced
ultrasound has also been reported, although data are
limited, and there is no current evidence to suggest
that contrast-enhanced ultrasound may improve the
detection of primary and metastatic HSA lesions in
dogs and cats.99,100
Screening for intrathoracic metastatic disease is also
very important prior to surgery in dogs and cats with
visceral HSA, as documentation of distant metastatic
disease (stage III patients) significantly alters progno-
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sis. Thoracic radiographs can be performed to screen
for pulmonary metastatic disease, and three-view tho-
racic radiographs have been shown to decrease the
incidence of false-negative diagnosis of pulmonary
metastatic disease as compared to one- or two-view
thoracic radiographs; in one study, three-view tho-
racic radiography was reported to have a 78% sen-
sitivity and 74% negative predictive value for pul-
monary HSA metastasis.101 An additional finding on
thoracic radiographs in patients with HSA can include
small size of the caudal vena cava in hypovolaemic
patients.
Advanced imaging with CT has also been reported
for screening of patients with HSA, and this modality
is being used more frequently in clinical practice for
staging of dogs and cats with this disease (Figure 2).
One study suggested that splenic HSA lesions may be
significantly less dense compared to nodular hyper-
plasia and haematoma on pre- and post-contrast
CT imaging.102 However, another study found no
significant differences in quantitative or categorical
CT data between malignant and benign splenic and
hepatic masses in dogs, such that advanced imaging
should be interpreted with caution.103 For atypical
sites of HSA (such as those occurring in bone, mus-
cle, cardiac tissues, thorax, retroperitoneum and oral
cavity), these advanced imaging modalities may be
needed to further characterize the primary tumour
and guide possible surgical treatment options.104 One
recent pilot study has also revealed a potential utility
of positron emission tomography-CT (PET-CT) with
18-fluorodeoxyglucose for staging and monitoring of
metastatic disease in dogs with splenic HSA following
splenectomy; in this study, abnormalities consistent
with metastatic disease were detected on PET-CT but
not conventional staging imaging modalities (tho-
racic radiographs and abdominal ultrasound) in some
patients, suggesting the potential for increased sensi-
tivity and earlier detection of metastatic disease with
PET-CT.105
Diagnosis of cardiac HSA is generally presumptive
in nature based on imaging findings and location.32
Patients with pericardial effusion secondary to cardiac
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F I G U R E 2 Preoperative CT scan images from a dog with a splenic mass (*): (a) transverse image, (b) multiplanar reconstruction
(sagittal) image, (c) multiplanar reconstruction () image. Note the cystic nature as well as the increased contrast enhancement of the mass
HSA often have a globoid cardiac silhouette on
thoracic radiographs, and distension of the caudal
vena cava may be seen in patients with cardiac
tamponade.106 Echocardiogram can be performed to
assess for cardiac HSA, although false negatives and
false positives are both possible.11,107 Echocardiogra-
phy has been reported to have a high sensitivity and
specificity for the diagnosis and differentiation of right
atrial and heart base masses in dogs with pericardial
effusion.108 One study showed a lower detection rate
of HSA lesions in the right auricle as compared to the
right atrium in dogs.31 Therefore, the lack of a visible
cardiac mass on echocardiography cannot completely
rule out the potential for cardiac HSA, especially in the
absence of pericardial effusion.
Electrocardiography can also be a valuable diag-
nostic tool for both assessments of patients with
cardiac HSA and other forms of visceral HSA. Find-
ings consistent with pericardial effusion (secondary
to rupture of cardiac HSA) can include reduced QRS
complex amplitude and electrical alternans, and
ventricular arrhythmias have been frequently docu-
mented in dogs with both cardiac and splenic forms
of HSA.74,75
Treatments and outcomes
Surgery
Surgery is a mainstay treatment for the majority of
dogs and cats with HSA (Figure 3). Pre-operatively,
Veterinary Record
cardiovascular stability should be assessed and
addressed with administration of intravenous flu-
ids, blood products and other therapeutic agents as
indicated. Electrocardiogram monitoring should be
performed pre-, intra- and post-operatively in dogs
undergoing splenectomy, with treatment of ventric-
ular arrhythmias as indicated; these arrhythmias
typically resolve within 24–48 h post-operatively.11,74
Surgical excision of all grossly abnormal tissue should
subsequently be performed.
For splenic HSA, total splenectomy is recom-
mended, and omental adhesions should be excised
en bloc with the spleen.11 The spleen should be han-
dled carefully to prevent iatrogenic rupture. Thor-
ough exploratory laparotomy should be performed
with excision of any representative lesions concern-
ing for metastatic disease in the liver, omentum or
other peritoneal tissues, especially if active haemor-
rhage is present.11 All excised tissues should be sub-
mitted for histopathology. Performing routine hepatic
biopsy in cases of suspected splenic HSA at the time
of splenectomy is often recommended for staging (due
to portal circulation and splenic drainage through
the liver); however, liver biopsies in grossly normal
appearing liver have been demonstrated to be low-
yield for HSA metastasis in dogs.109 Due to the nature
of global metastasis and prior abdominal contamina-
tion with neoplastic cells (especially in cases of tumour
rupture), peritoneal lavage is controversial. Peritoneal
lavage is recommended though in patients with other
sources of contamination or remnant blood/blood
clots to reduce the risk of peritonitis post-operatively.
Veterinary Record
F I G U R E 3 Intraoperative image of a large splenic
haemangiosarcoma immediately prior to splenectomy
Laparoscopic and laparoscopic-assisted techniques
for splenectomy have been reported in dogs with
small to moderately sized splenic HSA tumours.110,111
Laparoscopic splenectomy has also been documented
in cats.112 However, the indication for these mini-
mally invasive techniques is uncommon as the open-
ing into the abdomen is small, thereby precluding
easy removal of large splenic masses. Also, abdomi-
nal exploration and evaluation for metastatic disease
is limited in a minimally invasive approach.
For dogs with splenic HSA, reported median survival
times have ranged from 19 to 86 days with splenec-
tomy alone.23,53,113–115 For dogs with splenic HSA that
survive the immediate perioperative period, 2-month
and 1-year post-operative survival has been docu-
mented in 31% and 7% of dogs, respectively.116 Out-
come data are lacking in cats that undergo splenec-
tomy alone for HSA due to small representative case
numbers in feline studies on splenectomy, haemoperi-
toneum and HSA.25,45,48,68,117
Surgery can also be performed for excision of
primary cardiac HSA. Surgical resection of right
atrial/auricular appendage HSA lesions has been
reported, with potential for reconstructive procedures
following extensive resection.75,118–122 Several reports
have documented thoracoscopic right atrial and right
auricular mass excision in dogs with successful peri-
operative outcomes.120,122 In addition, pericardiec-
tomy techniques can be performed (either via a
minimally invasive or open approach) as a palliative
measure to prevent tamponade in patients with car-
diac HSA.123
For cutaneous HSA, surgical margins of 1–2 cm and
one fascial plane deep are generally recommended to
achieve complete excision.11 Alternatively, for subcu-
taneous and intramuscular HSA, wide excision (sim-
ilar to treatment of soft tissue sarcomas) is recom-
mended due to the potential for more invasive disease.
However, wide margins may be difficult to achieve in
these cases depending on the size of the lesion and
tumour location, such that less aggressive surgery and
adjuvant treatment may be considered.11,29
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The prognosis for dogs with dermal HSA appears
to be better than those with visceral HSA. After sur-
gical excision, median survival times of greater than
2 years have been reported, and dogs often die
due to other illness.29 Therefore, in contrast to dogs
with visceral HSA, surgical excision alone appears
to be a viable treatment option for patients with
cutaneous HSA. It is important to note, however,
that recurrent disease is common in dogs following
excision of dermal HSA, particularly in predisposed
breeds with multiple masses and masses in a ven-
tral location.54 Also, dogs with solar-induced lesions
have high loco-regional recurrence rates (up to 77%)
following excision, although prolonged survival has
been documented.54 Similarly, there appears to be an
improved prognosis for dogs with conjunctival HSA
(relative to visceral HSA) that undergo surgical exci-
sion alone, although recurrence is possible.124
For cats with cutaneous HSA, complete excision has
been associated with an improved outcome, and one
study reported a median survival time of >1460 days
for cats that underwent surgical excision of cutaneous
HSA.25,59 Vigilance is still warranted post-operatively
in these cases, however, as recurrence rates as high
as 60%–80% and metastasis have been reported fol-
lowing excision of dermal and subcutaneous HSA in
cats. Additionally, disease progression is more likely
in cases with subcutaneous involvement.25,45,58,60
As with dogs, conjunctival HSA in cats appears to
have a relatively improved prognosis compared to
visceral HSA, and surgical excision alone can be
curative.46
Chemotherapy and targeted therapy
Multiple chemotherapeutic protocols have been
described for treatment of HSA in dogs. With the
exception of dermal, non-invasive HSA without evi-
dence of metastatic disease, adjuvant chemotherapy
is generally recommended for patients with HSA due
to relatively poor outcomes with surgical excision
8 of 13
alone.11 The most common chemotherapy protocols
for HSA involve the use of doxorubicin (either as a sin-
gle agent or combination protocol) in both dogs and
cats. In cats with HSA, doxorubicin is typically used in
an adjuvant treatment setting, but studies are lacking
regarding the impact on metastatic progression and
survival in this species.11,25,48
The extent of the benefit incurred by adjuvant
chemotherapy treatment has been questioned. For
dogs with visceral HSA that undergo surgery and
adjuvant anthracycline-based chemotherapy, median
survival times are generally 141–179 days with less
than 10% of dogs surviving 12 months.18,125–134 How-
ever, the majority of these studies do not report a sta-
tistically significant improvement in survival time in
dogs with splenic HSA that are treated with surgery
and chemotherapy as compared to surgery alone.
One recent study suggested an improvement in sur-
vival time during the early follow-up period only (and
not when the entire follow-up time was assessed)
in dogs with splenic HSA treated with surgery and
chemotherapy as compared to surgery alone.115 Rel-
atively similar survival times of 183–189 days have
been found in dogs with primary cardiac HSA follow-
ing surgical excision and adjuvant doxorubicin-based
chemotherapy.31,118
With regard to non-visceral HSA, whereas purely
cutaneous tumours typically have a good progno-
sis with surgical excision alone, tumours with inva-
sion into the subcutaneous or intramuscular tis-
sues typically have a worse prognosis, and adju-
vant chemotherapy is often recommended in these
cases.11,19,29,135,136 However, outcomes for these dogs
still typically exceed those of dogs with visceral HSA
with median survival times of up to 307 days reported
for dogs with HSA extending into the muscular
tissue.29 For dogs with subcutaneous and intramuscu-
lar tumours that undergo surgical excision and adju-
vant doxorubicin treatment, median survival times of
as long as 1189 days and 272.5 days, respectively, have
been reported.136 For dogs with non-resectable sub-
cutaneous or intramuscular HSA, doxorubicin-based
chemotherapy can be used in a palliative and poten-
tially neo-adjuvant setting (with tumour size reduction
that may enable subsequent excision).137
Aside from intravenous administration of doxoru-
bicin, other forms of anthracycline drugs have been
evaluated for adjuvant treatment of dogs with splenic
HSA. One study found that epirubicin as an adjuvant
treatment for splenic HSA in dogs had similar activ-
ity compared to standard doxorubicin, although the
two study groups were dogs that underwent splenec-
tomy alone41 and dogs that received epirubicin fol-
lowing splenectomy,18 and no dogs were adminis-
tered doxorubicin for comparison.131 Also, seven of
18 dogs in the epirubicin group were hospitalized for
treatment of severe gastrointestinal signs.131 Another
study evaluated the use of intraperitoneal administra-
tion of pegylated liposome-encapsulated doxorubicin
in 14 dogs with splenic HSA following splenectomy.132
Of these dogs, 12 of 14 had hepatic metastases and
hemoabdomen at the time of death, demonstrating
Veterinary Record
that intra-abdominal metastasis still occurred.132 The
use of intravenous pegylated liposome-encapsulated
doxorubicin has also been evaluated as an adjuvant
therapy in dogs with splenic HSA. In 34 dogs, the
median survival time was determined to be 166 days,
and multiple adverse effects, including a desqua-
mating dermatitis and anaphylactic reactions, were
encountered.138
The addition of multiple other chemotherapeu-
tic agents to an adjuvant doxorubicin-based proto-
col has also been evaluated.125,127,129,133,139 One such
study showed an increased median time to metastasis
and median survival time in dogs treated with adju-
vant doxorubicin and dacarbazine therapy as com-
pared to those treated with adjuvant doxorubicin and
cyclophosphamide therapy.140 However, this study
included only 27 dogs (nine of which received dacar-
bazine) and dogs with varying anatomic location of
HSA (any abdominal organ or subcutaneous), and
the limitations of this study dictate the need for fur-
ther evaluation of dacarbazine as a treatment option
for HSA.140 The addition of COX-2 inhibitors to adju-
vant treatment protocols for dogs with HSA has also
been evaluated. One prospective study assessed the
outcome of 21 dogs that were administered a com-
bination of adjuvant doxorubicin and deracoxib fol-
lowing splenectomy for HSA and found an overall
median survival time of 150 days with no significant
difference in outcome based on stage of disease.141
The authors suggested that a median survival time
of 149 days in dogs with stage III HSA appears to
be longer than previously reported outcomes with-
out COX-2 inhibitor therapy, and further evaluation is
warranted.
Historically, non-doxorubicin and metronomic
based protocols have resulted in relatively decreased
improvement in survival time as compared to
doxorubicin-based protocols.142 However, anti-
angiogenic, metronomic therapies have been more
recently evaluated for treatment of dogs with HSA. One
study prospectively evaluated nine dogs with stage II
splenic HSA treated with adjuvant (post-splenectomy)
low-dose, oral chemotherapy (cyclophosphamide,
etoposide and piroxicam) and compared the out-
comes of these dogs to a retrospective control group
of 24 dogs with stage II splenic HSA treated with
adjuvant doxorubicin.126 The authors found statis-
tically similar median disease-free interval between
the two groups and significantly greater median sur-
vival time for dogs in the low-dose chemotherapy
group.126 Another recent retrospective study compar-
ing adjuvant (post-splenectomy) anthracycline versus
metronomic-based chemotherapy for dogs with stage
I and II splenic HSA found no significant difference in
the median time to progression of disease or median
survival time for these two groups.143 Two other
studies evaluating the outcome of dogs with splenic
HSA that received either doxorubicin alone post-
splenectomy or doxorubicin followed by metronomic
chemotherapy showed conflicting results.144,145 One
of these studies showed an increased median time
to metastasis and median survival time in dogs with
Veterinary Record
adjuvant doxorubicin and metronomic chemotherapy,
whereas the other showed no difference in outcome
between the two groups; these results may have been
influenced by differing disease stage in the patient
populations as well as the use of thalidomide in
conjunction with cyclophosphamide for only one of
the metronomic protocols.144,145 A recent study has
suggested an advantage to the use of thalidomide
after splenectomy in dogs as well, with five of 15
dogs surviving for greater than 1 year after surgery
when thalidomide was administered after surgery
until death.146 Thus, further evaluation regarding
the potential role of metronomic chemotherapy is
needed in animals with HSA, and it is possible that
adjuvant metronomic-based chemotherapy protocols
may result in similar to improved outcomes relative to
adjuvant doxorubicin-based chemotherapy in some
dogs with splenic HSA.
Adjuvant treatment of HSA in dogs with targeted
therapies has also been investigated, including via sev-
eral in vitro studies.147,148 One prospective study eval-
uated outcomes in dogs with stage I or II splenic HSA
treated with splenectomy, adjuvant doxorubicin (five
cycles) and subsequent toceranib administration if no
metastatic disease was detected at the time of dox-
orubicin completion.149 The authors found a median
disease-free interval of 161 days and median survival
time of 172 days for dogs that received toceranib,
and they concluded that these results appear to be
similar to outcomes of dogs that receive adjuvant
doxorubicin-based chemotherapy without adminis-
tration of toceranib.149 Another prospective study has
evaluated the administration of a drug that targets
sarcomas as well as tumour neovasculature (eBAT, a
bispecific angiotoxin) given to dogs with stage I-II
splenic HSA following splenectomy and prior to dox-
orubicin administration.150 The 6-month survival rate
for dogs of this study was approximately 70%, as com-
pared to less than 40% in the historical control group
that received doxorubicin only.150 Additional studies
on the use of targeted therapies are needed in com-
panion animals with HSA to further define a pos-
sible role of these medications in treatment of this
disease.
Immunotherapy
Although immunotherapy is not used regularly for
treatment of HSA in a clinical setting, there are
several studies that document a potential role for
immunotherapy in this disease. For instance, an HSA
vaccine was reported to elicit a humoral immune
response in dogs that received concurrent doxoru-
bicin for treatment of HSA.151 Another example
of immunotherapy for treatment of canine HSA
involves adjuvant use of liposome-encapsulated
muramyl tripeptide phosphatidylethanolamine (L-
MTP-PE), which has potential anti-metastatic activity
in this disease.128 The median survival time for dogs
treated with splenectomy, systemic chemotherapy
and immunotherapy with L-MTP-PE was 273 days.128
9 of 13
Furthermore, administration of single agent polysac-
charopeptide (in a non-adjuvant setting) has also been
suggested to delay the progression of metastasis and
prolong survival times in dogs with HSA.152 Additional
clinical studies are needed to evaluate the possible
role of immunotherapy in dogs and cats with HSA.
Radiation therapy
Rare reports of radiation therapy have also been doc-
umented for treatment of HSA in dogs. Palliative
(coarsely fractioned) radiation protocols have been
reported to cause a decrease in tumour size in some
cases of non-splenic HSA, although overall survival
has not been significantly prolonged.153 A possible
benefit of hypofractionated radiation in the setting
of cardiac HSA is that it may reduce the frequency
of cardiac tamponade requiring pericardiocentesis.154
Adjuvant definitive (full course) radiation therapy may
be considered in patients with narrow or incomplete
excisions of non-visceral HSA, although reports are
limited.135,136 Similarly to immunotherapy, additional
clinical experience and data are needed to further
evaluate the role of radiation therapy in dogs and cats
with HSA, and this treatment modality is used rarely in
clinical patients.
Overall prognosis and conclusion
Overall, the prognosis for patients with visceral HSA
is poor. Some studies have reported clinical stage
and histopathologic criteria (including nuclear pleo-
morphism, mitotic score, differentiation and grade)
as prognostic factors associated with survival times
in dogs with HSA, but these findings are not consis-
tent across studies.115,128,134 Primary hepatic and pri-
mary cardiac HSA have a similarly poor prognosis,
although renal HSA may have a relatively improved
prognosis given a decreased frequency of concur-
rent haemoperitoneum and distant metastatic disease
at diagnosis.11,37,75 Alternatively, primary retroperi-
toneal HSA appears to have a poor prognosis with
high rates of local recurrence and metastasis and
short survival times.33 In the majority (77%) of
cats with visceral HSA, the disease has metastasized
by the time of diagnosis, and most cats are not
treated with chemotherapy.48 The prognosis for vis-
ceral HSA is poor in cats, with the majority of patients
dying from tumour recurrence or metastasis.25,45,48,117
For cats that present with spontaneous haemoperi-
toneum, the prognosis is guarded.68 Alternatively, cats
and dogs with non-infiltrative cutaneous HSA can
have a good prognosis with surgical excision, and
adjuvant therapy is not typically indicated in these
patients.25,29,54,59
In conclusion, HSA remains a disease with a gener-
ally poor prognosis in both dogs and cats, although
some forms of HSA behave in a less aggressive
fashion with improved outcomes. Surgical excision
and anthracycline-based chemotherapy remain the
10 of 13
mainstays of treatment, although novel treatment
modalities involving metronomic therapy, targeted
therapy, immunotherapy and radiation therapy are
currently under investigation and show promise for
potential roles in treatment of this disease.
CONFLICT OF INTEREST
The authors declare that there is no conflict of interest
that could be perceived as prejudicing the impartiality
of the research reported.
AUTHOR CONTRIBUTIONS
Design work with co-authors, drafting, revising and
final approval of the manuscript: Maureen A. Griffin,
William T. N. Culp and Robert B. Rebhun. Responsible
for overall content: Maureen A. Griffin.
ORCID
William T. N. Culp https://orcid.org/0000-0001-
6132-156X
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How to cite this article: Griffin MA, Culp WTN,
Rebhun RB. Canine and feline
haemangiosarcoma. Vet Rec. 2021;e585.
https://doi.org/10.1002/vetr.585