Cutaneous T-cell Lymphoma With Sezary

Syndrome in a Dog
Aiden P. Foster’
Ellen Evansz
Roy L. Kerlin3
David M. Vail‘

An 8-year-old female spayed Cocker Spaniel mix breed dog was presented with generalized
erythroderma, scaling and alopecia. Radiographs of the thorax demonstrated a discrete lung mass
which was aspirated using ultrasound guidance and cytological analysis revealed large abnormal
lymphocytes. Similar cells were observed in the peripheral blood and in skin biopsies. The cells in the
skin biopsies were epidermotropic, indicative of an uncommon cutaneous lymphoma termed
cutaneous T cell lymphoma (CTCL), sometimes also called mycosis fungoides. lmmunohistochemical
staining of a skin biopsy was positive for the CD3 antigen demonstrating that the lymphocyte infiltrate
was of a T-cell lineage. The presence of neoplastic lymphocytes in the epidermis and peripheral blood
indicate that this is a rare variant of Cutaneous Epidermotropic Lymphoma (CEL) called Sezary
syndrome based on nomenclature used in the human literature. An unusual feature of this dog, not
seen in previous cases, was the presence of a discrete neoplastic lung mass.

Key Words: Canine cutaneous T-cell lymphoma, Sezary syndrome, mycosis fungoides

Introduction
The term Cutaneous T-cell Lymphoma (CTCL) is
used to describe a group of T-cell malignancies recog-
nized in humans and occasionally in dogs,’,‘ cat^,^,^
h a m s t e r ~ , ~ , ~ cattle,6h o r ~ eand
, ~ a ferret.loA num-
ber of terms have previously been used to describe
CTCL including mycosis fungoides, Sezary’s syn-
drome, cutaneous reticulum cell sarcoma and dermal
T-cell lymphoma, however it is now believed that these
diseases all represent a spectrum of the same disease
process. The most important feature of CTCL is clonal
neoplastic T-cell proliferation usually presenting initial-
ly in the skin. The development of CTCL may include
either local growth in the skin from a plaque into a
tumor with or without hematogenous spread. The
pathogenesis of CTCL in humans, in part, includes
attraction of neoplastic T-cells to the epidermis and the
binding of intercellular adhesion molecule-1 (ICAM-1)
and MHC II molecules on the surface of keratinocytes
with lymphocyte function antigen-1 (LFA-1) and CD4
expressed by the lymphocytes. The neoplastic T-cell
involved in CTCL without leukemic spread (previously
called mycosis fungoides) has been reported as hav-
ing a Th, phenotype whereas the spread of T-cells into
the peripheral blood (sometimes called Sezary’s syn-
drome) is associated with the Th, phenotype.’l
Clinically CTCL may be described according to the
extent of epidermal infiltration, inflammatory response,
systemic spread and local growth. The plaque stage
CTCL is the variant usually referred to as mycosis fun-
goides and is characterized by sharply demarcated
discoid plaques. The CTCL clinical variant termed
Sezary’s syndrome usually includes generalized exfo-
liating erythroderma, intense pruritus, peripheral lym-

’Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 2015 Linden Drive West,
Madison, Wisconsin 53706
‘Schering-Plough Research Institute, P.O. Box 32, Lafayette, New Jersey 07848
3Drug Safety Evaluation, Central Research Division, Pfizer, Inc, Eastern Point Road, Groton, Connecticut 06340
Dr. Foster’s corresponding address is: Division of Companion Animals, Department of Clinical Veterinary Science, University
of Bristol, Langford House, Langford, Somerset, BS 18 7DU, United Kingdom.
Continued

PAGE 188 Vol. 26,No. 4,1997 VETERINARY CLINICAL PATHOLOGY

 Cutaneous T-cell Lymphoma
phadenopathy and abnormal hyperchromatic mononu-
clear cells in the skin and peripheral blood.
In the dog the most common clinical presentation of
CTCL is a generalized erythematous exfoliative der-
matitis; multiple plaques and nodules can also be
observed. The term Cutaneous Epidermotropic Lym-
phoma (CEL) has sometimes been used in the dog in
preference to CTCL because the presence of T-cells is
usually inferred unless immunohistochemistry demon-
strates the type of lymphocyte present. There are three
previous case reports of canine CTCL resembling
human Sezary's syndrome, this report documents a
fourth case of CTCL with Sezary's syndrome which
was positive for CD3 antigen, a marker for T-cells, and
had a neoplastic mass in the I ~ n g . ' ~ - ' ~
Case Report
An 8-year-old female spayed Cocker Spaniel mix
breed dog was presented to the dermatology service
of the Veterinary Medical Teaching Hospital (VMTH) at
the University of Wisconsin-Madisonfor evaluation of a
generalized dermatitis of 5 months' duration. The skin
disease had been diagnosed as chronic sebaceous
adenitis and the patient was referred because the skin
disease continued to worsen despite therapy.
The history included the development of focal areas
of alopecia on the right shoulder, medial carpus, and
ventral abdomen. A clinical diagnosis of dermatophyto-
sis was made and the dog received 750 mg griseoful-
vin daily for two weeks, however, new lesions devel-
oped on the trunk. Skin biopsies were obtained from
crusty alopecic lesions and submitted for histologic
analysis, and the findings were suggestive of chronic
sebaceous adenitis. The dog was treated with vitamin
A capsules (8,000 units per day) for 2 months with no
beneficial effect on the skin disease. The dog then
became pruritic and the skin lesions reported included
areas of focal alopecia with scaling and papules. Skin
scrapings and a fungal culture were negative for mites
and fungal pathogens respectively. Over the next 2
months, the skin lesions of alopecia, scaling and
papules spread over the whole body and the dog did
not respond to antibacterial drugs (cephalexin,
enrofloxacin), prednisolone or etretinate therapy. The
etretinate was administered for 18 days .
On initial presentation the dog was reported to be
persistently licking its body particularly the legs, face
and along the dorsum; the dog's appetite was poor.
The dermatologic examination revealed generalized
alopecia, erythema, fine (thin) large scales especially
on the trunk and multiple focal patches of crusting and
ulceration (Fig. 1) . The dog was quiet, the rectal tem-
VETERINARY CLINICAL PATHOLOGY
perature was 103.6 degrees F and the dog weighed
11 kg. Apart from the presence of generalized periph-
eral lymphadenopathy, the remainder of the physical
examination was within normal limits.
The initial diagnostic evaluation of the case included
routine radiographs of the thorax and abdomen which
revealed a focal, soft tissue mass in the caudodorsal
lung fields at the level of the 8th and 9th intercostal
space, adjacent to the thoracic wall; there were no
intraabdominal abnormalities seen. The radiographic
interpretation of the thorax was of a primary pul-
monary neoplasm or atypical pulmonary lymphoma.
Thoracic ultrasound demonstrated a circumscribed
area of hyperechoic pulmonary consolidation measur-
ing approximately 2.5 cm in the left caudodorsal lung
field which was interpreted as a fungal granuloma or
neoplasm. An ultrasound guided aspirate of the mass
was submitted for cytology. The aspirates of the pul-
monary mass contained blood and were otherwise
moderately cellular (Fig. 2). Most cells present were
large, round cells with round cleaved, or folded nuclei
containing stippled chromatin and occasional promi-
nent nucleolar rings. They had scant to moderate
amounts of pale blue cytoplasm which was frequently
finely granular and occasionally contained fine pink
granules. A clear Golgi zone was seen adjacent to the
nucleus of some cells. Free cytoplasmic droplets and
lysed cells were also present. A diagnosis of lym-
phoma was made.
A complete blood count (CBC), serum chemistry
panel and analysis of urine collected by cystocentesis
was carried out. A moderate normocytic, nor-
mochromic nonregenerative anemia, consistent with
anemia of chronic disease, was present. There was a
leukocytosis characterized by a neutrophilia with a
slight left shift, lymphocytosis and monocytosis. Many
of the lymphocytes were large and contained folded or
cleaved nuclei with fine chromatin and prominent
nucleolar rings. Lymphoid leukemia or lymphoma with
a leukemic blood picture were suspected on the basis
of the lymphocyte numbers and morphology. A concur-
rent inflammatory response was also present. No sig-
nificant abnormalities were noted on the serum chem-
istry panel or urinalysis results.
Three 6 mm punch skin biopsies were collected
from the dorsum of the trunk and submitted for
histopathology. Biopsies were taken from three sites
where the lesions were most severe. All sections
extended from the epidermis to the panniculus adipo-
sus. Within the dermis there was a dense accumula-
tion of infiltrating lymphocytes that tended to be close
to the dermal epidermal junction and concentrate
around hair follicles and apocrine glands. In many
Continued
Vol. 26, No. 4,1997 PAGE 189
 Cutaneous T-cell Lymphoma

cells displaced the keratinocytes

and formed small clusters
termed “Pautrier’s microab-
scesses” (Fig 3). It was notewor-
thy that lymphocytes infiltrated
into the epithelium of the exter-
nal root sheath of hair follicles
and also into the apocrine gland
epithelium. The lymphocytes
were large and moderately pleo-
morphic with a large folded, or
cleaved nucleus and moderate
amounts of cytoplasm. Mitotic
figures were fairly common and
many individual cells were
necrotic. Although apocrine
glands were present, there were
no sebaceous glands in these
sections. Representative tissue
sections were analysed for CD3
immunoreactivity by a previous-
ly reported imm-unohistochemi-
FIG. 1 - Photograph of dog illustrating generalized erythema (erythroderma), alopecia and scal-
cal t e c h n i q ~ e .This
’ ~ confirmed
ing of the head.
the lymphocyte infiltrates were
of the T-cell lineage.
Previo us biopsies of “crusty”
skin lesions in this dog collected
4 months earlier were reviewed
and revealed atrophy and loss
of sebaceous glands with
marked peri-adnexal fibrosis
and inflammation consistent
with the diagnosis of sebaceous
adenitis. There was no evidence
of neoplasia in the skin biopsies
taken at that time.
The preliminary diagnosis
was thoracic lymphoma and the
owners elected to take the dog
home for euthanasia; the biop-
sies subsequently confirmed
cutaneous epidermotropic lym-
phoma.

FIG. 2 - Photomicrograph of peripheral blood smear from a dog with epitheliotropic lymphosar-
coma. A neutrophil and three neoplastic lymphocytes are shown. The lymphocytes are large and Discussion
their nuclei contain finely stippled chromatin. One nucleus is cleaved; prominent nucleolar rings
are seen in another nucleus. (Wright-Giemsa stain, original magnification 630x, oil objective). The diagnosis of CTCL in the
dog is usually made in middle-
aged or older individuals, of
areas, the lymphocytic cells infiltrated into the epider- either sex and any breed.16Unfortunately, the progno-
mis, often obliterating the distinction between dermis sis for this disease is very poor and animals usually do
and epidermis. In regions where the epidermal infil- not survive more than several months beyond diagno-
trate of lymphocytes was most marked, the neoplastic sis despite various kinds of the~apy.’~.‘~
Clinical signs of
Continued

PAGE 190 Vol. 26,No. 4,1997 VETERINARY CLINICAL PATHOLOGY

 CutaneousT-cell Lymphoma

this case are typical of previ-

ous reports in that general-
ized exfoliative erythroderma
with pruritus was observed.
The diagnosis is usually con-
firmed by the demonstration
of epitheliotropic lymphocytes
in the epidermis especially in
small groups called Pautriers’
microabscesses, although
the latter are not present in
every case.19 Three clinical
forms of canine CTCL are
recognized and characterized
by either oral/mucocutaneous
ulcers, generalized exudative
dermatitis or multiple cuta-
neous nodules; these three
forms are probably temporal
stages Of a progressive dis- FIG. 3 -This is a high magnification view of the epidermis (E) and dermis (D).The neoplastic lym-
ease which is unresponsive phocytes infiltrate into the epidermis separating keratinocytes and almost obscuring the dermo-epi-
to therapy. dermal junction. Haematoxylin and Eosin. Original magnification 400x.
There are several unusual
features of this case, one of which is the previous his- partly because it was only given for 18 days; therapy
tological report of sebaceous adenitis. This is an for sebaceous adenitis usually takes at least four to
uncommon skin condition of unknown etiology that can eight weeks to be effective.21The major drawbacks
have a distinct clinical presentation depending upon with retinoid therapy are the costs of therapy and the
the breed involved. In short-coated breeds of dog, potential for adverse side effects.
such as vizslas, lesions are usually annular areas of The second interesting feature of this case is that it
scaling and alopecia that tend to coalesce with time. In would appear to meet the criteria for the form of CTCL
standard poodles there is marked hyperkeratosis fol- termed Sezary’s syndrome. Only three other cases
lowed by alopecia; lesions appear on the head and have been previously reported with this syndrome in
progress along the neck and dorsal trunk. Akitas tend the d0g.12-14The presence of both malignant T-cells in
to have extensive hair loss, generalized erythema and the skin and the peripheral circulation are the impor-
greasy coat.16 Sebaceous adenitis is associated with tant criteria for this syndrome both in the dog and in
the development of progressive sebaceous gland human patient^.'^.^^ In this case the use of immunohis-
destruction. Initially there is lymphocytic granuloma- tochemistry techniques confirmed the presence of T-
tous or pyogranulomatous inflammation that eventual- cells in the skin; similar findings in skin biopsies from
ly resolves and subsequently the sebaceous glands one other case of canine Sezary’s syndrome have
are no longer observed histologically. Thus the clinical been reported.”
signs associated with this disease include alopecia, A third interesting feature of this case is the pres-
crusting, scaling and occasionally bacterial follic~litis.’~ ence of the pulmonary mass containing cells with sim-
Therapy for this condition is often unrewarding ilar morphology to the cells observed in the skin and
although some cases appear to respond to synthetic peripheral blood. The cytologic analysis of the lung
retinoids, particularly isotretinoin.’6,z0~z1
The synthetic mass was available before the CBC and skin biopsy
retinoids have also been used in dogs with CTCL with reports. In one other case report of canine Sezary’s
some success in terms of palliation and extension of syndrome there was diffuse infiltration of the lungs
life expectancy.20,21One of the biopsy sections taken 4 with neoplastic lymphocytes but this finding was
months prior to referral was made available for exami- reported post mortem and immunohistochemistry was
nation and the histologic findings were considered not carried out to confirm the presence of T-cells in the
suggestive of sebaceous adenitis. It is conceivable that skin.14
this patient had both sebaceous adenitis and CTCL; it The similarities between canine CTCL and human
may have had a poor response to etretinate therapy CTCL have prompted several immunohistochemical
Continoed

VETERINARY CLINICAL PATHOLOGY Vol. 26, No. 4,1997 PAGE 191

 CutaneousT-cell Lymphoma
studies, as the requisite reagents have become avail-
able, to study canine CTCL as a model for the human
disease. Histological analysis of canine CTCL patients
demonstrated the cerebriform or convoluted nuclear
contours of tumor cells that have been associated with
human T-cell n e ~ p l a s i a . ’ ,The
~ , ~use
~ of immunohisto-
chemical techniques has demonstrated that, as in this
case, CTCL in canine patients have T-cell infiltrates
that are positive for CD3 cell
Furthermore there is substantial expression of the
integrin CD18 by dermal and epidermal malignant T-
cells and their ligand ICAM-1 which could be important
in terms of the pathogenesis of canine epidermotropic
T-cell n e o p l a ~ i a . ’ ~
The
. ~ ~unusual
. ~ ~ feature of canine
CTCL compared to the human disease is that the CD
&T-cell immunophenotype predominates in the T cell
infiltrate of human skin lesions while CD 8’ T cells
were consistently detected in one study of canine
CTCL.’3
Treatment for CTCL in human patients may rely
upon local (topical) treatment or systemic treatment,
and since the disease is usually progressive, patients
generally receive both types. Local therapy may
include topical chemotherapy, local or whole body X-
ray irradiation and photochemotherapy (PUVA).zzIn
one case of canine Sezary syndrome low-energy
orthovoltage radiation therapy was associated with a
clinical response but the dog became leukopenic and
septicemic and died shortly thereafter.” Systemic
chemotherapy has been tried in a variety of forms and
in both canine and human patients appears to be
associated with significant palliation of the disease but
not prolonged s u r v i ~ a 1 . ~ ~ ~ ~ ~ ~ ~ ~
ACKNOWLEDGMENTS
The advice of Dr. K.A. Moriello in the investigation of this case and the preparation of
this case report is gratefully acknowledged.Theradiology sewice of the VMTH are thanked
for their assistance in diagnostic evalution of this case
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