Paper 188 DISC

Veterinary Dermatology 2000, 11, 291297

Case report
Cutaneous presentation of canine intravascular
lymphoma (malignant angioendotheliomatosis)
YVONNE A. VANGESSEL,* SEAN P. M C DONOUGH,* HANNAH J. M C CORMICK{
and BRIAN A. SUMMERS*
*Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
{Saranac Veterinary Clinic, 3900 Route 3, PO Box 67, Saranac, NY 12981, USA
(Received 12 May 1999; accepted 16 June 1999)

Abstract A 9-year-old female spayed Boxer dog presented with variably sized, rm, black, raised, exudative
subcutaneous masses on her head, neck and trunk, that tended to uctuate in size and frequently ulcerate.
Skin biopsy showed that the dermis was expanded by a densely cellular mass of proliferative capillaries
distended with large pleomorphic neoplastic round cells mixed with brin and erythrocytes. Intravascular
lymphoma was diagnosed and immunostains were compatible with a CD8+ T lymphocyte histogenesis
(CD3+/CD79a7/TCRab+/CD8a+). Post-mortem examination, four months after diagnosis, revealed
neoplastic T-cells within meningeal arteries. We are unaware of other reports of a cutaneous presentation
and ante-mortem diagnosis of intravascular lymphoma in the dog. Additionally, this vasoproliferative form of
intravascular lymphoma has not been previously described in dogs.
Keywords: CD3 complex, dog, intravascular lymphoma, immunohistology, malignant angioendotheliomatosis,
skin disease.

INTRODUCTION
Intravascular lymphoma (IVL), originally called
neoplastic or malignant angioendotheliomatosis due
to a suspected endothelial histogenesis, is a rare fatal
disease characterized by intravascular proliferation of
neoplastic lymphocytes in the absence of a solid
primary tumour or detectable neoplastic cells in
peripheral blood. This intravascular proliferation
ultimately results in vascular compromise of the
aected tissue secondary to thrombus formation and
luminal occlusion.
IVL has been reported in dogs,17 one cat8 and more
frequently in humans.9,10 Aected dogs most commonly present with acute central nervous system signs.
In all reported canine cases, diagnosis of IVL was
made at necropsy by the histological identication of
neoplastic lymphocytes lling variably sized cerebromeningeal arteries and veins. In most cases there was
also widespread but clinically silent involvement of the
vessels of parenchymal organs. There is no description
of skin lesions in any of these reports.
Two clinically distinct presentations of IVL are
described in humans: neurologic and cutaneous.
Patients with the neurologic form of IVL often

Correspondence: S. P. McDonough, Department of Biomedical

Sciences, Cornell University, Ithaca, NY 14853. Tel.: (607) 253
4299; E-mail: spm13@cornell.edu; Fax: (607) 2533357
# 2000 Blackwell Science Ltd

present with mental sluggishness, dementia, cerebrovascular accidents or seizures. In the cutaneous form
patients typically present with painful plaques or
nodules resembling phlebitis, panniculitis or vasculitis.10 In both instances there is generally widespread
involvement of parenchymal organs and ante-mortem diagnosis is usually made via skin or lung biopsy.
The majority of reported cases of canine IVL
resemble the neurologic form of IVL described in
people with no reported description of a cutaneous
manifestation. In all reported cases of canine IVL
diagnosis was made at post-mortem examination.
Here we describe a case of ante-mortem diagnosis of
IVL in a dog with cutaneous lesions, which was
conrmed four months later at necropsy.
CASE REPORT
A 9-year-old female spayed 25 kg Boxer dog was
presented to the Saranac Veterinary Clinic (Saranac,
NY) with a one-month history of multiple, variablysized, black, raised cutaneous masses. Initially the
dog had approximately 12 1.5 cm diameter alopecic
dark red to black hyperpigmented areas distributed
dorsally over the head and neck, and randomly on
the trunk. These areas were nonpruritic and nonpainful, and developed into rm black plaque-like
masses, which tended to uctuate in size, ooze serum,
scab and ulcerate.
291

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292

Y. A. vanGessel et al.
(Fig. 1). The dermal mass dissected both into the
subcutaneous adipose tissue and the overlying supercial dermis. The central area of the neoplasm
featured a dense disorderly proliferation of thinwalled vascular channels lined by plump fusiform
cells (Fig. 2a). These vascular channels contained
large round pleomorphic cells mixed with red blood
cells and brin. The vasoformative nature of this
lesion was claried by immunohistochemical stains
for smooth muscle actin, which identies vascular
pericytes (Fig. 2b).
At the margins of the neoplasm, the diagnostic
pattern of conspicuous large round mononuclear cells
occluding the lumen of capillaries could be discerned
(Fig. 3a). The intraluminal cells were approximately
1215 mm in diameter and had sparse cytoplasm and
a round to oval indented stippled nucleus occasionally containing 12 prominent nucleoli. The mitotic
rate was variable, averaging 1 mitosis per high power
eld. The proliferative vascular channels were lined
by von Willebrand Factor (vWF) antigen positive
endothelial cells (Fig. 3b) and smooth muscle actin
positive cells, presumably pericytes or myocytes. In
contrast, the intravascular cells were negative for
vWF antigen and smooth muscle actin. Consistent
with an IVL of T-cell origin, the intravascular
neoplastic cells were CD45RA and CD3 positive
(Fig. 3c) and CD79a negative. Additionally, the
neoplastic cells were strongly positive for the newly
described canine b2-integrin ad.11
A diagnosis of cutaneous IVL was made and oral
prednisone therapy (10 mg given orally three times
daily tapered to 10 mg given orally every other day

At the time of presentation the dog had no other

signicant medical problems. Results of a complete
blood count and serum chemistry were within normal
ranges. A full thickness excisional skin biopsy from the
left ank fold was obtained under general anaesthesia
and xed in 10% neutral buered formalin. Prolonged
and excessive bleeding from the surgical site was noted
at the time of biopsy and the dog was given 30.0 mg
vitamin K (Phoenix Pharmaceuticals Inc, MO) subcutaneously. Examination three days later revealed
marked subcutaneous oedema of both mammary
chains and the left hind limb, enlargement of the left
inguinal lymph node and a fever of 103.58 F. The dog
was treated with 500 mg Cephalexin (Nolvopharm,
Toronto, Canada) given orally three times daily for 10
days and these signs resolved.
The biopsy was submitted to the Surgical Pathology Service at Cornell University, where it was
trimmed, embedded in paran, sectioned at 6 mm
and stained with haematoxylin and eosin (H & E)
according to standard laboratory procedure. Immunohistochemical stains were performed using a
streptavidin-horseradish peroxidase technique (DAKO,
Carpinteria, CA) and manufacturer's instructions
(Table 1). Negative technique controls were performed by substituting the primary antibody with
either normal rabbit serum or mouse ascites raised
against an irrelevant antigen. Positive tissue controls
consisted of normal canine spleen and lymph node.
Histologically the specimen was comprised of ulcerated haired skin overlying a multilobulated, unencapsulated, densely cellular, inltrative, deep dermal
mass with large areas of necrosis and haemorrhage
Table 1. Immunohistochemistry

Paran
embedded
tissue
sections

Antigen

Antibody

Antigen
Retrieval

Dilution

Source

vWF

pAb
Rabbit
mAb
1A4
mAb
CA4.1D3
mAb
HM57
pAb
Rabbit
mAb
CA18.3C6

Trypsin

1: 1000

DAKO (Carpinteria, CA)

NT

1: 40

DAKO (Carpinteria, CA)

MW
CSA
MW
CSA
Trypsin

1: 200

PF Moore (Davis, CA)

1: 200

DAKO (Carpinteria, CA)

1: 200

DAKO (Carpinteria, CA)

CSA

1: 200

PF Moore (Davis, CA)

mAb
CA17.2A12
mAb
CA15.8G7
mAb
CA20.8H1
mAb
CA13.1E4
mAb
CA9.JD3
mAb
CA15.4G2

NT

1: 10

PF Moore (Davis, CA)

NT

1: 10

PF Moore (Davis, CA)

NT

1: 10

PF Moore (Davis, CA)

NT

1: 10

PF Moore (Davis, CA)

NT

1: 10

PF Moore (Davis, CA)

NT

1: 10

PF Moore (Davis, CA)

SMA
CD45RA
CD79a
CD3
ad

Frozen
tissue
sections

CD3
TCRab
TCRgd
CD4
CD8a
CD8b

vWF = vonWillebrand's Factor, SMA = Smooth muscle actin, MAb = monoclonal antibody, PAb = polyclonal antibody,
NT = no treatment, MW = microwave, CSA = catalysed signal amplication (DAKO, Carpinteria, CA).
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Canine intravascular lymphoma

293

Figure 1. Skin biopsy. The supercial

and deep dermis are inltrated by a
densely
cellular
unencapsulated
multilobular mass (H & E 6 7.5).

(Mutual Pharmaceutical Inc, PA)) was started 3

weeks post-biopsy in an attempt to control the
development of new lesions and the progression of
older ones. Treatment was unsuccessful and the
masses continued to enlarge, most notably on the
right shoulder and forelimb, growing to 10 cm in
diameter over several months. Despite a good
appetite, gradual weight loss was noted. Eventually
the dog became anorexic and depressed, and was
euthanized four months after initial diagnosis.
A full necropsy was performed. Beyond the skin
masses, no additional gross lesions were noted. Skin,
lung, liver, kidney, spleen, heart, brain, pancreas,
adrenal gland, thyroid gland, lymph node and
intestine were harvested. Multiple sections of each
organ were embedded in Tissue-Tek O.C.T. compound embedding medium for frozen tissue specimens (Miles, Elkhart, IN) and snap frozen in 2
methylbutane, which was prechilled to the point of
freezing in liquid nitrogen or xed in 10% buered
formalin. Sections of formalin xed tissue from each
organ were stained with H & E and examined
microscopically. The histological skin lesions were
similar to those previously described. In addition,
within a single frontal lobe brain section, neoplastic
cells lled a medium sized meningeal artery within a
sulcus (Fig. 4). Immunophenotyping on the formalin
xed brain tissue showed these cells were CD3+ T
lymphocytes, similar to those in the skin. All other
tissues examined were unremarkable.
Immunostains on frozen tissue sections further
characterized the neoplastic cells in the skin lesion as
TCRab+, TCRgd7, CD8a+, CD8b+, and CD47.
Neoplastic cells were not present in the samples of

brain that had been frozen. The nal diagnosis was

dermal and cerebral IVL of CD8+ T-lymphocyte
histogenesis.
DISCUSSION
IVL is a rare form of lymphoma in the dog. Of the 19
cases in the literature, 15 cases have been reported
only in abstracts with minimal description of the
clinicopathologic presentation. In the four detailed
case reports,1,2,5,6 aected dogs were adults of various
breeds and of both sexes. Two dogs presented with
neurologic signs1,5 characterized by progressive hindlimb ataxia and prosencephalic signs including
depression, listlessness and head pressing. One of
these dogs had spontaneous intraocular haemorrhage
and apparent blindness.1 The third dog presented
with bilateral retinal detachments,2 and the fourth
with right forelimb lameness.6 Of 17 cases of canine
IVL immunophenotyped at Cornell University and
reported in abstract form,3 45% of aected dogs
presented with ataxia, 27% with seizures, 15% with
central vestibular disease, 10% with blindness and
10% with severe depression and several dogs
presented with multiple signs (McDonough, unpublished data). None of the dogs reported had
cutaneous lesions and the diagnosis was established
at post-mortem in all cases.
The clinicopathological syndrome was remarkably
dierent in the present case. In this 9-year-old female
spayed Boxer dog, a series of haemorrhagic skin
masses brought the dog to veterinary attention and an
ante-mortem biopsy provided a denitive diagnosis of
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Y. A. vanGessel et al.

Figure 2. Higher magnication at the

centre of the dermal mass shown in
Figure 1.(a) Note the proliferation of
fusiform cells forming vascular channels
which contain red blood cells, brin and
scattered large pleomorphic round cells
(arrows) (H & E 6 210); (b) Smooth
muscle actin immunostaining of the mass
accentuates the vascular channels which
contain mononuclear neoplastic cells
(DAB,
counterstained
with
Gill's
haematoxylin 6 210).

IVL of T-cell type. In this case the histological

diagnosis was dicult. When the skin lesion was rst
studied, a diagnosis of haemangiosarcoma was
seriously considered. The lesion more closely resembled an unusual manifestation of cutaneous
haemangiosarcoma than a cutaneous lymphoma
because of the gross appearance of the lesions,
excessive bleeding after biopsy and the massive
vascular proliferation seen on microscopic examination. However a presumptive diagnosis of dermal IVL
was made based on the presence of intravascular
neoplastic mononuclear cells, which were seen most
clearly at the margins of the tumour lobules. This
diagnosis was conrmed with immunostaining, which
demonstrated proliferation of both endothelial cells
and pericytes and identied the intravascular neoplastic cells as CD8+ T-lymphocytes.
A striking vascular proliferation has occasionally
been described in human cases of IVL.10,12 The exact
stimulus of this exaggerated vascular response
remains unknown. Histologically the response does
# 2000 Blackwell Science Ltd, Veterinary Dermatology, 11, 291297

not resemble recanalization of a large thrombosed

vessel, and a capillary response of this magnitude is
not usually appreciated secondary to infarction.
Postulated pathogeneses include an endothelial proliferative response to a product of the neoplastic cells
or atypical response to vaso-occlusion.10 When rst
described, IVL was mistakenly believed to be a
unique neoplastic proliferation of intravascular endothelial cells and was thus named malignant
angioendotheliomatosis. It was not until the mid1980s, when immunohistochemistry became more
widely available, that the neoplastic cell was identied as a lymphocyte in both dogs and humans.1,13
The recently increased number of canine lymphocyte markers has allowed more precise immunophenotyping of canine lymphoma. Immunophenotyping
of 15 cases of canine IVL classied eight as T-cell, six
as nonB-nonT-cell and 1 as a B-cell lymphoma.3 In
this case, the neoplastic cell was a CD8+ T cell. These
results are in striking contrast to the situation in
humans where IVL is predominantly a B cell

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Canine intravascular lymphoma

295

Figure 3. Margin of the dermal mass

shown in Figure 1.(a) Neoplastic round
cells are mixed with erythrocytes within
vascular channels. (H & E 6 420); (b)
vonWillibrand
Factor
positive
endothelial cells line the vascular
channels, while the intravascular
neoplastic cells are vWF negative
(DAB, counterstained with Gill's
haematoxylin
6 540);
(c)
The
intravascular neoplastic cells are CD3
positive, compatible with a T-cell origin
(DAB, counterstained with Gill's
haematoxylin 6 210).

lymphoma. These results are consistent with the

observations that, in the dog, T-cell lymphomas are

proportionately more common than in man, and tend

to be CD8+.14
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Y. A. vanGessel et al.

Figure 4. Frontal lobe of brain. Neoplastic

T-cells occlude a meningeal artery (H & E
6 270).

Veterinarians, especially veterinary dermatologists

and pathologists, should be aware that canine IVL
can present as a dermatologic disorder in the absence
of neurologic signs. IVL must be included in the
dierential diagnosis of cutaneous neoplasms, most
notably when haemangiosarcoma is being considered
both clinically and histologically. Although the
histological diagnosis may be dicult, a presumptive
diagnosis of IVL can be made on H & E stained tissue
sections and should be conrmed with immunostains.
As canine IVL has not previously been diagnosed
ante-mortem, prognosis is unknown. Progression of
the disease in this dog suggests that systemic
chemotherapy, as for other forms of canine lymphoma, may be warranted. The possibility of antemortem diagnosis of canine IVL via skin biopsy will
help to establish the prognosis and possible treatment
options for this rare canine disease.

ACKNOWLEDGEMENTS
The authors would like to thank Dr Peter Moore,
Department of Pathology, Immunology and Microbiology, UC Davis for providing leukocyte markers,
Christina A. Smith, Department of Biomedical
Sciences, Cornell University, for excellent quality
immunohistology, and Alexis Wenski-Roberts, Image Lab, Cornell University, for assistance with
illustrations. This work was partially funded by the
Alumni Association, Cornell University.

3.

4.

5.
6.

7.
8.

9.

10.

11.

REFERENCES
1. Dargent, F.J., Fox, L.E., Anderson, W.I. Neoplastic
angioendotheliomatosis in a dog: an angiotropic
lymphoma. Cornell Veterinarian 1988; 78: 25362.
2. Kilrain, C.G., Saik, J.E., Jeglum, K.A. Malignant
angioendotheliomatosis with retinal detachment in a
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12.

dog. Journal of the American Veterinary Medical

Association 1994; 204: 91821.
McDonough, S., Summers, B., Van Winkle, B.,
Valentine, B., vanGessel, Y. Immunophenotypic
heterogeneity of canine intravascular lymphoma
(malignant
angioendotheliomatosis).
Veterinary
Pathology 1998; 35: 438 (Abstract).
McGrath, J.T., Van Winkle, T., Morse, C. Malignant
intravascular lymphoma (malignant angioendotheliomatosis) in the dog. Veterinary Pathology 1989; 40: 134
(Abstract).
Summers, B.A., Lahunta, A. Cerebral angioendotheliomatosis in a dog. Acta Neuropathologica 1985; 68: 104.
Steinberg, H. Multisystem angiotropic lymphoma
(malignant angioendotheliomatosis) involving the
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Investigation 1996; 8: 5025.
Summers, B.A., de Cummings, J.F., Lahunta, A.
Veterinary Neuropathology. St. Louis: Mosby 1995 394.
Lapointe, J.M., Higgins, R.J., Kortz, G.D., Bailey,
C.S., Moore, P.F. Intravascular malignant T-cell
lymphoma (malignant angioendotheliomatosis) in a
cat. Veterinary Pathology 1997; 34: 24750.
Fredricks, R.K., Walker, F.O., Elster, A., Challa, V.
Angiotropic intravascular large cell lymphoma
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an angiotropic intravascular lymphoma: Immunohistochemical, ultrastructural, and genetic studies.
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Canine intravascular lymphoma
13. Bhawan, J., Wol, S.M., Ucci, A.A., Bhan, A.K.
Malignant lymphoma and malignant angioendotheliomatosis: One disease. Cancer 1985; 55: 5706.
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Histologic classication and immunophenotyping of

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Resume Une femelle Boxer, sterilisee, agee de 9 ans, est presentee pour l'apparition de masses sous-cutanees
fermes, noires, en relief et exudatives, de taille variable, localisees sur la tete, le cou et le tronc, ayant tendance
a uctuer et a s'ulcerer. Des biopsies cutanees ont montre une invasion cellulaire dermique par des masses
denses de capillaires proliferatifs et distendus par de grandes cellules rondes neoplasiques, pleomorphes,
melangees a de la brine et a des erythrocytes. Un diagnostic de lymphome intravasculaire est fait. Les
immunomarquages sont compatibles avec une origine lymphocytaire T CD8+ des cellules neoplasiques
(CD3+/CD79a/TCRab+/CD8a+). Une autopsie realisee 4 mois apres le diagnostic a montre des cellules T
neoplasiques dans les arteres des meninges. Il s'agit du premier rapport de lymphome intravasculaire associe a
des signes cutanes diagnostique ante-mortem chez le chien. En outre, cette forme vasoproliferative de
lymphome intravasculaire n'a pas ete precedemment rapportee chez le chien. [vanGessel, Y. A., McDonough,
S. P., McCormick, H. J. et Summers, B. A. Cutaneous presentation of canine intravascular lymphoma
(malignant angioendotheliomatosis). (Signes cutanes d'un lymphome intravasculaire (angioendotheliomatose
maligne) chez un chien.) Veterinary Dermatology 2000; 11: 291297.]

Resumen Una perra Boxer de 9 anos, castrada, se presento con masas subcutaneas exudativas de tamano
variable, duras, negras y elevadas, en la cabeza, cuello y tronco, que tend an a uctuar de tamano y
frecuentemente ulceraban. La biopsia cutanea mostro que la dermis se encontraba engrosada por una masa
celular densa de capilares proliferativos dilatados con celulas redondas pleomorcas, neoplasicas, de gran
tamano, mezcladas con brina y eritrocitos. Se diagnostico un linfoma intravascular y las inmunotinciones
fueron compatibles con una histogenesis de linfocitos T CD8+ (CD3+/CD79a/TCRab+/CD8a+). El
examen post-mortem, cuatro meses despues del diagnostico, revelo celulas T neoplasicas en las arterias
men ngeas. No tenemos conocimiento de otras descripciones de diagnostico ante-mortem de linfoma
intravascular en el perro. Por otra parte, esta forma vasoproliferativa de linfoma intravascular no ha sido
descrita anteriormente en el perro. [vanGessel, Y. A., McDonough, S. P., McCormick, H. J. e Summers), B.
A. Cutaneous presentation of canine intravascular lymphoma (malignant angioendotheliomatosis).
(Presentacion cutanea del linfoma intravascular canino (angioendoteliomatosis maligna).) Veterinary
Dermatology 2000; 11: 291297.]
Zusammenfassung Eine neunjahrige, kastrierte Boxerhundin wurde mit harten, schwarzen, exsudativen,
subkutanen, in der Grosse variierenden und haug ulzerierenden Knoten am Kopf, Nacken und Rumpf
vorgestellt. Hautbiopsien ergaben, dass die Dermis durch eine dichte, zellulare Masse proliferierender
Kapillaren, die mit grossen, pleomorphen, neoplastischen, mit Fibrin und Erythrozyten vermischten
Rundzellen angefullt und erweitert waren, ausgedehnt wurde. Intravaskulares Lymphom wurde
diagnostiziert und Immunfarbungen waren mit einer CD8+ T-Lymphozytenhistiogenese kompatibel
(CD3+/CD79a/TCRab+/CD8a+). Postmortale Untersuchung vier Monate nach der Diagnose ergab
neoplastische T Zellen in menigealen Arterien. Berichte von kutanen Symptomen und ante-mortem Diagnose
von intravaskularem Lymphom beim Hund sind uns nicht bekannt. Ausserdem wurde diese vasoproliferative
Form eines intravaskularen Lymphoms bisher beim Hund nicht beschrieben. [vanGessel, Y. A., McDonough,
S. P., McCormick, H. J. und Summers, B. A. Cutaneous presentation of canine intravascular lymphoma
(malignant angioendotheliomatosis). (Kutane Symptome eines kaninen, intravaskularen Lymphoms (maligne
Angioendotheliomatose.) Veterinary Dermatology 2000; 11: 291297.]

# 2000 Blackwell Science Ltd, Veterinary Dermatology, 11, 291297