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Clinical communication — Kliniese mededeling
Lymphangiosarcoma in a 3.5-year-old Bullmastiff bitch with vaginal
prolapse, primary lymph node fibrosis and other congenital defects
J H Williamsa*, J Birrellband E Van Wilpec
INTRODUCTION
Lymphangiosarcoma is an extremely
rare, generally aggressive malignant
tumour which has been reported in hu-
mans3,5,19,26, only 16 dogs1,4,8,9,14–18,20,22,24,27,29,
a similar number of cats19,11,12,25,28,2
horses13,23, and a cow21. Lymphangio-
sarcoma in dogs, with comparison with
that in humans, is reviewed in a compan-
ion article30. The tumour arises from lym-
phatic lining endothelium, often in the
skin or subcutis, and was originally
reported in humans by Stewart and
Treves in 1948 in patients having had
chronic lymphoedema of extremities
after radical mastectomy for breast carci-
noma, which had included lymph node
resection and/or radiation, thereafter
becoming known as ‘Stewart-Treves’
syndrome3,5,19,26. Lymphangiosarcoma in
humans has also occasionally arisen fol-
lowing lymphoedema of other origins
such as primary lymphoedema due to
defects in development of the lymphatic
system, or secondary to the likes of
inflammatory disease, surgical proce-
dures, trauma, idiopathic, congenital
pathology or filarial infestations5. In most
cases lymphangiosarcoma rapidly invades
and infiltrates adjacent tissues and meta-
stasises via haematogenous and lym-
phatic routes internally, often involving
the chest, but other organs and cavities
mayalsobeinvolved5,12,13,23,30.Themajority
of reported feline cases, however, pre-
sented as tumours of the caudoventral
abdominal wall10–12,25,28. Mean survival
time after diagnosis and/or surgery is
generally short in most species and the
overallprognosis, as in humans, is consid-
ered poor3to extremely poor26.
The 1st canine case was reported by
Kelly in 198115, with only sporadic reports
since then. Most cases were in medium to
large breed dogs with ages ranging from 8
weeks to 13 years but with a slight majority
in male dogs and dogs 5 years or older30.
Only 1 canine case was related to primary
congenital dysplasia of the lymphatic sys-
tem, that being in a 4-year old Bouvier des
Flandres described by Webb et al in 200429
with aplasia of the popliteal lymph nodes.
However, lymphoedema in dogs due to
primary lymphatic system dysplasia is
recognised7, the defect most commonly
being small or absent lymph nodes, with
lymph node fibrosis being reported as the
initial defect, and leading to secondary
lymphatic obstruction. Very few cases of
lymphangiosarcoma arising from primary
lymphoedema have been reported in
humans3. Primary lymphoedema pre-
dominates in human pubertal females,
suggesting an oestrogenic link19 but a simi-
lar sex predisposition has not been found
0038-2809 Jl S.Afr.vet.Ass. (2005) 76(3): 165–171 165
aDepartment of Paraclinical Sciences, Section of Pathol-
ogy,Faculty of Veterinary Science, University of Pretoria,
Private Bag X04, Onderstepoort, 0110 South Africa.
E-mail: june.williams@up.ac.za
bPO Box 12991, Onderstepoort, 0110 South Africa.
E-mail: jrbirrell@polka.co.za
cElectron Microscopy unit, Faculty of Veterinary Science,
University of Pretoria, Onderstepoort, 0110 South Africa.
E-mail: erna.vanwilpe@up.ac.za
*Author for correspondence.
Received: May 2005.Accepted August 2005.
ABSTRACT
Lymphangiosarcoma is an extremelyrare tumour in dogs with only 16 cases reported in the
literature.Lymphoedema,which may be primary due to defectsinthelymphaticsystem,or
secondary to various other pathologies, often precedes malignancy. Of the 16 canine
reports, only 1 dog was confirmed as having had prior primary lymphoedema due to
aplasia of the popliteal lymph nodes. A case of lymphangiosarcoma is described in a
3.5-year-old purebred, Bullmastiff bitch which presented with vaginal blood ‘spotting’ for
3 weeks after cessation of oestrus, during which intromission by the male had been unsuc-
cessful. During ovariohysterectomy a large multicystic, proliferative, spongy, fluid-filled,
brownish-red mass surrounding the cervix and projecting into the abdominal space was
removed with the cervix, and a diagnosis of lymphangiosarcoma made on histological and
electron microscopic examination of the tissue. Ultrastructurally, no basement membrane
or pericytes were found, only some of the neoplastic endothelial cells were linked by tight
junctions while there were gaps between others, and neither micropinocytotic vesicles nor
Weibel-Palade bodies occurred in the cells examined. Very few of the endothelial cells lining
the many interlinking, tortuous maze of channels, stained slightly positive immuno-
histochemically for factor VIII-related antigen. The channels were filled mostly with serous
fluid, and occasionally mixed leucocytes and some erythrocytes. The endothelium was
often associated with underlying blocks of collagenous material, as well as loosely-
arranged aggregates of lymphocytes, other mononuclear cells and occasional neutrophils
in the connective tissue septae and more prominently perivascularly. The bitch was
discharged on antibiotic treatment but returned 2 weeks later with apparent prolapsed
vagina which failed to reduce over the next week. Laparotomy revealed the tumour to have
spread extensively in the caudal abdomen to involve the broad ligament and the ventral
rectal serosa, and the ‘prolapsed’ tissue was found to be expanded vaginal wall. The bitch
was euthanased and necropsied, Histological examination confirmed lymphangio-
sarcomatous invasion of the submucosal and muscular layers of the retroperitoneal,
traumatised,prolapsedpartofthevagina, the urethra and the ventralrectalwall.Thebroad
ligament was diffusely invaded with tumour which had proliferated into the caudal
abdominal space, and 3 small intra-trabecular foci of tumour were found in the right
popliteal lymph node near the hilus. Mitotic figures were generally scarce. There was mild
subcutaneous oedema of the ventral trunk extending from the axillae to the inner proximal
thighs, which had not been evident clinically, and the lymph nodes (peripheral more
so than internal) microscopically showed marked trabecular and perivascular fibrosis
especially in hilar regions. Other congenital defects were hepatic capsular and central
venous fibrosis with lymphatic duplication and dilatation in all areas of connective tissue,
ventrally-incongruous half-circular tracheal rings, and multifocal renal dysplasia affecting
the right kidney. There was locally-extensive subacute pyelonephritis of the left kidney.
Key words: cervix, congenital defects, dog, histopathology, lymphangiosarcoma, lymph
node fibrosis, lymphoedema, ultrastructure, vagina.
Williams J H, Birrell J, Van Wilpe E Lymphangiosarcoma in a 3.5-year-old Bullmastiff bitch
with vaginal prolapse, primary lymph node fibrosis and other congenital defects.Journal
of the South African Veterinary Association (2005) 76(3): 165–171 (En.). Department of
Paraclinical Sciences, Section of Pathology, Faculty of Veterinary Science, University of Pre-
toria, Private Bag X04, Onderstepoort, 0110 South Africa.
in lymphoedematous dogs7.
Chronically lymphoedematous tissue is
prone to recurrent infection due to it
being protein-rich, as well as to the
associated impairment of the local immune
system and regional immunosurveil-
lance6,19,29,31. Lymphangiosarcoma appears
in most species to arise most commonly in
anatomical regions having been lymph-
oedematous, whether of primary or sec-
ondary origin, and especially in humans,
this is often of long duration5. This suggests
that lingering protein-rich interstitial
fluid and/or chronic physical pressure on
lymphatic endothelium may be stimuli
for neoplastic transformation8.
CASE HISTORY
A 3.5-year old purebred Bullmastiff
bitch with no apparent inbreeding in the
3 preceding generations and with no
previous medical history of disease, was
presented to the 2nd author 3 weeks after
oestrus, during which the male had made
unsuccessful attempts at mating due to
unsuccessful intromission. She had then
‘spotted’blooddropletsfromhervulvaaf-
ter cessation of oestrus, which had raised
concern in her owner. At presentation she
was playful, eating well, and with no sys-
temic signs of disease. On clinical exami-
nation, rectal temperature was normal,
the bitch was panting and all peripheral
lymph nodes palpated (submandibular,
superficial cervical and popliteal) were
unremarkable.She was in good body con-
dition but with a slightly dull haircoat.
A mass in the caudal abdomen was
palpated but not precisely located. The
vulva appeared normal in size, with no
fresh blood when examined, however
blood was noticed when the dog moved
around in the hospital kennel. Ovario-
hysterectomy was performed, during
which the ovaries and uterine horns were
normal in size and appearance, but t he cer-
vix was approximately 5 cm in diameter,
due to a soft, proliferative, irregular,
brown-red serosal surface with multiple
fluid-filled cystic structures (Fig. 1). Most
of the cervix was excised and submitted
for histopathological examination, where
a diagnosis was made of suspected
lymphangiosarcoma, based on both H&E
and immunohistochemical staining for
factor VIII antigen. Scattered colonies of
bacterial rods were seen under light mi-
croscopy in some sections in some of the
more necrotic areas of tumour where
there was also a predominance of neutro-
phils. The cervical mucosal glands were
mildly distended, with some containing
eosinophilic proteinaceous material with
occasional red blood cells. The tumour
did not extend to the cervical lumen, sub-
mucosa or subjacent inner 1/3 of smooth
muscle. She was discharged on a week’s
course of broad spectrum antibiotics.
Approximately 14 days later the bitch
was returned to the veterinarian due to
development of an apparent vaginal
prolapse; she was admitted for daily
cleansingandattemptsatreductionofthe
proplapsed tissue, which only illicited
tenesmus and re-prolapse after each
reduction. A laparotomy was performed
7daysafteradmissionwiththeaimofper-
forming an internal vaginopexy. During
laparotomy, however, it was discovered
that the prolapsed tissue was actually
expanded vaginal wall, and similar
fluid-filled friable red-brown cystic masses
as had been found surrounding the
cervix, were now evident involving the
tissues around the stump of the vagina,
and along the serosa of the base of the
intra-abdominal rectum. The bitch was
euthanased with an overdose of barbitu-
rate while under general anaesthesia and
necropsied the following morning.
Macroscopic necropsy findings
The body condition of the bitch was
good, with the only external abnormalities
being the prolapsed vaginal tissue which
was erythematous, haemorrhagic and
ulcerated, and the evidence of abdominal
midline surgery (Fig. 2). Subcutaneous
tissuesoftheventraltrunk, caudo-ventral
abdomen and inner thighs were mildly
oedematous, and perivaginal and peri-
rectal deep tissues were oedematous and
haemorrhagic. The inguinal lymph nodes
appeared to be congested with moderate
perinodal oedema; however, lymph node
size of all peripheral and internal abdomi-
nal nodes was unremarkable.
The caudal abdomen internally showed
diffuse red-brown, soft, irregular, serous-
fluid-filled neoplastic tissue involvement
166 0038-2809 Tydskr.S.Afr.vet.Ver. (2005) 76(3): 165–171
Fig. 1: Serial transverse sections of post-ovariohysterectomy formalinised cervix with
irregular lymphosarcomatous proliferation of outer mural and serosal regions.
Fig. 2: Traumatised prolapsed portion of vagina due to mural invasion by lymphangio-
sarcoma.
of the broad ligament , the stump of the
vagina and a locally-extensive, elliptical,
plaque-like area (10 × 4 cm) of the
intra-abdominal ventral rectal serosa
(Fig. 3), as had been seen involving the
cervix submitted previously for histo-
pathology. The bladder wall was con-
tracted with marked serosal congestion
and mural muscular hyperplasia. The
remaining genital tract along with
bladder and rectum, were dissected out
completely, including all surrounding
retroperitoneal, intrapelvic tissues, and
fixed in 10 % buffered formalin.
Other pathological findings of note
were moderate size-discrepancy between
left and right kidneys, with the right
kidney being firm, pale, irregular and
apparently fibrotic, and at least 1/3
smaller than the left. A large wedge-
shaped area of medullo-cortical necrosis
was situated in the middle of the left
kidney (Fig. 4). There was mild mitral
valvular endocardiosis with mild left
ventricular eccentric hypertrophy and
moderate left papillary muscular hyper-
trophy. The tracheal cartilaginous rings
were all narrow and each petered out at
the ventral midline of the trachea, with
successive cartilaginous half-circles alter-
nating with each other. Being a brachy-
cephalic breed, there was mandibular
prognathism and also mild bilateral
internal hydrocephalus. On faecal flota-
tion, a few Ancylostoma caninum eggs were
found.
Microscopic findings
With routine haematoxylin and eosin
(H&E) staining, the intra-abdominal areas
of tumour involving serosal surfaces of
the cervix, broad ligament, and ventral
rectum comprised numerous interlinking
channels lined discontinuously by elon-
gated, variable-sized, spindle-shaped
cells with plump oval to round vesicular
nuclei and prominent, large and mainly
singlenucleoli(Fig.5).Inplacesthesecells
piled up on each other and there was
invasion into the tunica muscularis layers
of both rectum (Fig. 6), urethra and repro-
ductive tract and in several areas also into
the submucosa, with the cells mostly
lining small open, vacant spaces, and
surrounding bundles of muscle fibres and
small regular blocks of collagen, in this
way dissecting its way into tissues. Several
of the neoplastic cells appeared multinu-
cleated (2 or more nuclei were counted), or
were piled up alongside each other with
indistinct cell borders. Mitotic figures
were generally scarce, ranging from 0 in
most fields, to up to 4 in some high-power
fields (×40) in more anaplastic regions of
the tumour, and some of the mitoses were
bizarre. The channel lumens mostly
0038-2809 Jl S.Afr.vet.Ass. (2005) 76(3): 165–171 167
Fig. 3: Stump of uterus, broad ligament and ventral rectal serosal involvement with
lymphangiosarcoma 3 weeks after ovariohysterectomy.
Fig. 4: Shrunken right kidney due to multifocal cortical dysplasia; focally-extensive wedge
of pyelonephritis of non-dysplastic left kidney.
Fig. 5: Extra-cervical lymphangiosarcoma showing neoplastic endothelial cells lining
fluid-filled channels containing occasional leucocytes (H&E, ×20).
appeared empty but within some there
was pale amorphous eosinophilic mate-
rial, while others contained haemolysed
blood or a few intact red blood cells,
and/orscatteredlymphocytesandplasma
cells as well as occasional neutrophils.
The interstitial stromal areas were oede-
matous, sometimes haemorrhagic and
with moderate numbers of loosely aggre-
gated mononuclear round cells (lympho-
cytes, plasma cells and macrophages),
variable numbers of neutrophils, and there
was fairly marked interstitial mono-
nuclear perivascular cuffing. Vascular
endothelium of blood vessels supplying
the areas of tumour was hypertrophic
with nuclei being plump and vesicular.
Many blood vessels within the inter-
stitium displayed neutrophilic leucostasis
and some areas of tumour were necrotic.
Retroperitoneally, lymphangiosarcoma
was found multifocally throughout
smooth muscle and fibrous connective
tissue of the wall of the vagina including
the caudal proplapsed region, along with
marked vascular congestion, haemorrhage
and oedema affecting especially the
traumatised prolapsed part. This region
had overlying mucosal ulceration and
necrosis and chronic-active subluminal
granulation tissue. The neoplastic cells
made rudimentary scattered, poorly-
connecting or large inter-connecting
channels, extending in parts right up to
the ulcerated mucosa. Similar scatterings
of lymphocytes and plasma cells as seen
in the abdominal regions of the tumour
were present in the intervening tissues
and most channels were empty or con-
tained only a few red blood cells. The
outer smooth muscle layers of the urethra
were also invaded by tumour, and 3 small
trabecular foci of lymphangiosarcoma
were found in the right popliteal lymph
node near the hilus (Fig. 7).
Immunohistochemical staining of the
tumour with factor VIII-related antigen
showed strong positive granular intra-
cytoplasmic staining of all vascular endo-
thelial cells in the interstitial tumour
stroma, but only very few neoplastic
lymphatic endothelial cells had very
slight cytoplasmic granular positivity
(Fig. 8).The left mandibular (right was not
sampled), left and right inguinal, left and
right popliteal, sublumbar and supra-rectal
lymph nodes as well as a small node in the
region caudo-dorsal to the cervical area
had atrophic cortical lymphoid tissue and
moderate to marked trabecular and
perivascular fibrosis especially involving
medullary and hilus regions; this latter
change being more prominent in the
peripheral than the intra-abdominal
nodes (Fig. 9). Medullary sinuses and
trabecular lymphatics in all nodes were
168 0038-2809 Tydskr.S.Afr.vet.Ver. (2005) 76(3): 165–171
Fig. 6: Rectal serosal, muscular tunic and submucosal invasion by lymphangiosarcoma
(H&E, ×4).
Fig.7: Trabecular foci of lymphangiosarcoma (H&E, ×4) of the right popliteal lymph node.
Fig.8: Factor VIII-related antigen immunoperoxidase staining of lymphangiosarcoma (×10)
showing strong vascular endothelial positivity but negligible neoplastic endothelial
staining.
distended due to oedema, as well as with
red cells in the caudal intra-abdominal
nodes, and sinus histiocytosis was
common. Some nodes (mandibular and
inguinal) had a moderate amount of
intracellular melanin pigment at the
cortico-medullary junctions and others
had intracellular haemosiderin; evidence
of prior blood breakdown. The sublumbar
lymph node showed perinodal/extracap-
sular tumour invasion. Unfortunately,
skinfrom the oedematous area of the ven-
tral trunk was not sampled.
Other significant histopathological
findings included severe ascending puru-
lentpyelonephritisoftheleftkidney,with
occasional adjacent areas of subacute
lymphoplasmacytic interstitial nephritis
and fibrosis. There was multifocal renal
cortical dysplasia of the small left kidney,
displaying typical foetal glomeruli, inter-
stitial fibrosis, scattered rudimentary
tubules, protein casts and little inflamma-
tory change.
The liver revealed moderate pericentral
to midzonal hydropic cytoplasmic change
in hepatocytes, as well as moderate to
marked multifocal central venous fibrosis
with venous and especially lymphatic
duplication, and lymphatic dilatation in
several portal triads as well as in areas of
capsular fibrosis. There was peri-arterio-
lar lymphoid sheath (PAL) lymphocyte
depletion in the spleen with prominent
ellipsoids surrounding each PAL.
Ultrastructural findings
Electron microscopy of the intra-
abdominal tumour revealed slit-like
spaces lined by spindle-shaped cells,
with some nuclei exhibiting prominent
nucleoli (Fig. 10). No basal lamina was
found lining the spaces and pericytes
were also absent in the sections screened.
Some of the neoplastic cells were joined
by tight junctions (Fig. 11), while others
had large gaps between them. Pinocytotic
vesicles and Weibel-Palade bodies could
not be demonstrated in the tumour cells
examined. Lymphocytes and neutrophils
were found within some of the cell-lined
spaces as well as in the interstitium.
DISCUSSION
This case appears to be the 2nd report of
lymphangiosarcoma in a dog related to
primary congenital dysplasia of the
lymphatic system – the 1st being that in a
4-year old spayed female Bouvier des
Flandres, which had aplasia of the
popliteal lymph nodes, and which had
manifested hind limb oedema from the
age of 8 weeks29. It had a lymphangio-
sarcomatous inguinal mass which had
beennoticedonly45dayspriortoreferral.
The bitch reported currently was not
0038-2809 Jl S.Afr.vet.Ass. (2005) 76(3): 165–171 169
Fig.9: Right popliteal lymph node (H&E, ×4) showingmarked medullary and hilar trabecular
and perivascular fibrosis.
Fig.10: Ultrastructure of lymphangiosarcoma showing spaces lined by neoplastic cells.
Note prominent nucleoli, gaps between some of the cells and absence of a basal lamina.
Fig.11: Electron microscopic scan of lymphangiosarcoma showing tight junctions (arrows)
between neoplastic cells and absence of a basal lamina.
apparently recently inbred according to
her pedigree papers, which registered the
previous 3 matings on both dam and sire
side. She had appeared healthy up to the
time of the recent oestrus, apart from a
mild hookworm infestation which may
have been the cause of the dull haircoat at
the time of initial presentation. The 1st
sign of any problem had been the failure
of intromission by the male during that
oestrus due to narrowing of the vaginal
lumen, and thereafter the vaginal blood
‘spotting’. She had the unusual presenta-
tion of post-ovariohysterectomy vaginal
prolapse due to progressive tumour inva-
sion of the wall, making attempts at re-
duction impossible. The small foci of
tumour in the trabeculae of the right
popliteal lymph node may possibly have
arrived there due to back pressure reflux
from the intra-pelvic tumour. Subcutane-
ous oedema of the ventral trunk and me-
dial hind limbs was relatively mild at
necropsy and had never been noticed
clinically. It may be speculated that the
lymph node fibrosis affecting internal ab-
dominal lymph nodes may have caused
an underlying low-grade clinically unob-
trusive oedema of the reproductive tract
which may have worsened under the
hormonal influence of oestrogen during
oestrus, and these cumulative factors may
have been the trigger for neoplasia.
Lymph node fibrosis has been mentioned
as a primary lymph node anomaly in
humans2and in dogs with primary
lymphoedema7,wherethesmall shrunken
lymph nodes have an increased amount
of fibrous tissue in the hilum2, much like
that found in this case. This bitch also had
other congenital anomalies including
hepatic lymphatic and vascular derange-
ments, unilateral renal dysplasia and
abnormally-formed tracheal cartilagi-
nous rings. Similar genetic studies as in
man, for example, in which the FOXC2
and VEGFR-3 gene autosomal dominant
mutations were found in human ‘lymph-
oedema-distichiasis’ syndrome31, would
be an interesting comparative exercise in
dogs with multiple congenital defects
which include dysplasia of the lym-
phatic system. The origin, in humans, of
some simple lymphoedemas or chylous
refluxes, as in chylothorax, chylous
ascites, chyle reflux into limb lymphatics,
in the kidneys (chyluria) and the uterus
and vagina (chylo-metrorrhagia), has
been ascribed to congenital or acquired
abnormalities of the central abdominal or
thoracic collecting ducts2. Unfortunately
specific macroscopic and microscopic
examination of abdominal and thoracic
lymphatic trunks were not done in the
bitch of this report. Very occasional human
postmastectomy cases of lymphangio-
sarcoma had no clinical history of lymph-
oedema, or oedema had subsided several
years prior to onset of the tumour5.
More attention focussed on possible
abnormalities of the lymphatic system in
future cases of canine lymphangio-
sarcoma is warranted. Lymphatic neopla-
sia should be considered as a differential
diagnosis in all cases of non-resolving
lymphoedema, this case being unusual in
that the primary site involved the repro-
ductive tract and presented as failure to
breed and vaginal prolapse after ovario-
hysterectomy. Most other cases have pre-
sented with subcutaneous oedema or a
fluctuant subcutaneous mass and/or
clinical signs related to thoracic effusion.
Early, and if necessary, repeated biopsy
and histopathological examination of any
non-resolving oedematous mass, skin, or
subcutaneous tissue and careful investi-
gation of pleural or abdominal tissue
oedemas with effusions in dogs and other
species is recommended for diagnosis of
lymphangiosarcoma.
ACKNOWLEDGEMENTS
Marie Smit of the histopathology labo-
ratory of the Department of Pathology at
the Onderstepoort Faculty of Veterinary
Science is thanked for the immuno-
histochemical staining of the sections,
and Joey Breedt, Peter Mokonoto and
Rephima Phaswane from the same labo-
ratory are thanked for their contribution
in producing the H&E sections. The help
of the departmental secretary, Elma
Vorster, with the manuscript and electronic
formatting, is much appreciated, and
Charmaine Vermeulen of the audio-visual
section is gratefully acknowledged for
her patience and effort with the photo-
graphs.
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