ttp://www.bsava.

com REVIEW

Significant advances in veterinary

oncology – 60 years on
J. M. Dobson

Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, UK

Corresponding author email: jmd1000@cam.ac.uk

The first edition of the Journal of Small Animal Practice published in February 1960, contained a paper
entitled “Recent Treatments of Malignant Neoplasia” by Dr Larry Owen. Now we have reached the 60th
anniversary of JSAP, that article provides a baseline from which to review subsequent advances in
veterinary oncology, which includes worldwide networks that have resulted in veterinary oncology
becoming the multidisciplinary speciality that it is today. There certainly have been many advances in
understanding of the pathology and epidemiology of animal cancers and in methods of diagnosis and
treatment. However, the subject has become so large and diverse that not all aspects can be covered
in detail here. It should also be acknowledged that there are still many gaps in knowledge in this field
and that, because of a lack of randomised clinical trials, the evidence base for what is often regarded
as “standard of care” is weak.

Journal of Small Animal Practice (2019)

DOI: 10.1111/jsap.13076
Accepted: 31 July 2019

INTRODUCTION skin (37.5%), female genital (including mammary) (25.9%)

Historical background
The first edition of JSAP (February 1960) contained a paper
entitled “Recent Treatments of Malignant Neoplasia” (Owen
1960). Owen stated that “surgical treatment is the most satisfactory
method but this may not be possible in every case” and described var-
ious forms of radiotherapy, hormonal therapy and chemotherapy
that were being used in animals and human patients at that time.
Larry Owen became one of the pioneers of veterinary and com-
parative oncology, gaining World Health Organisation recogni-
tion for the Department of Veterinary Medicine at the University
of Cambridge and leading development of both radiotherapy and
chemotherapy in the treatment of cancer in domestic animals.
Therefore, as we approach the 60th anniversary of the JSAP, his
article provides a fitting starting point to review advances in vet-
erinary oncology over the past 60 years.
In the introduction to his paper, Owen states that “A controlled
study of the behaviour of all forms of malignant neoplasia is desirable
as a background to the true assessment of therapy”. This was written
at a time when an understanding of the epidemiology and pathol-
ogy of cancer in animals was in its infancy. The previous year Ear-
nest Cotchin had published a survey of 4187 tumours from dogs
and 571 from cats examined in the Royal Veterinary College’s
Department of Pathology in the period 1940 to 1958 (Cotchin
1959). The three most common tumour sites in dogs were the
and alimentary (14%) and, in the cat: alimentary (28.7%) skin
(24.5%) and lymphatic (12.3%) He concluded that “the rarity of
cancer of the lung, stomach, large intestine or uterus in dogs and cats
contrasts with their importance in human beings, … some tumours
that are common in dogs and cats but rare in man would appear to
provide detailed study, such as mast cell tumours of the skin of dogs
…”. Cotchin suggested that a picture was emerging of what types
of neoplasm were important in dogs and cats in “the diagnostic
catchment area of the London College”, and made various pro-
posals for the advancement of research including the preparation
of a definitive atlas of animal tumours and the development of
animal tumour registries.
Current status
Nowadays, cancer is recognised as an important cause of mor-
bidity and mortality in cats and dogs, accounting for 27% of all
deaths in purebred dogs in the UK (Adams et al. 2010), a pro-
portion similar to that derived from a post mortem series of 2000
dogs, in which 23% of all dogs and 45% of dogs over 10 years of
age, died of cancer (Bronson 1982). Other epidemiological stud-
ies based on hospital populations or on surveys of intakes into
pathology laboratories, are largely supportive of these estimates
for the dog population as a whole (Dorn et al. 1968, Priester &
McKay 1980, Goldschmidt & Shofer 1992, Bonnett et al. 1997,
Reid-Smith et al. 2000), as are recent figures from a number of

Journal of Small Animal Practice • © 2019 British Small Animal Veterinary Association 1
 J. M. Dobson
European Tumour Registries (Merlo et al. 2008, Vascellari et al.
2009, Bronden et al. 2010). In the absence of reliable historical
tumour registries, it is difficult to know whether the prevalence
of cancer in cats and dogs has actually increased over the past
60 years. A number of factors may contribute to an increase in
the diagnosis of cancer in cats and dogs. For instance, as a result
of improvements in health and welfare, animals are living longer
and cancer is generally a disease of older age (Bonnett & Egen-
vall 2010). Veterinary medicine has seen many advances in the
past 60 years that have resulted in increasing specialism within
the profession and this is exemplified in veterinary oncology with
the development of clinical specialists and specialist hospitals.
Changes in society, the introduction of pet health insurance and
the advent of the internet have changed client expectations along
with clinical approaches. Whilst increasingly advanced techno-
logical options are available for treatment of the cancer patient,
there is also an increasing awareness of the importance of quality
rather than quantity of life and, in this context, the value of pal-
liative care.
The Veterinary Cancer Society (VCS) was formed in 1976 by a
small group of veterinarians whose goal was to establish a profes-
sional organisation dedicated specifically to veterinary oncology
and to encourage research and collaboration between its members.
VCS now represents nearly 1000 specialists in surgical, medical
and radiation oncology, internists, pathologists, pharmacologists
and general practitioners from around the world. Within Europe
the European Society of Veterinary Oncology (ESVONC) was
founded in 1992 by a group of scientists active in the field of
veterinary and comparative oncology. Like the VCS, ESVONC
encourages research, collaboration and education in veterinary
oncology and comparative oncology though an annual congress
and support of the journal Veterinary and Comparative Oncol-
ogy, launched in 2003. In 1988, veterinary medical oncology
FIG 1. Time line depicting key events in the history of veterinary oncology
2 Journal of Small Animal Practice • © 2019 British Small Animal Veterinary Association
became a specialism its own right through the American College
of Veterinary Internal Medicine, which grants specialty certifica-
tion in veterinary oncology and currently oversees 32 approved
residency training programmes in oncology. Likewise in Europe,
veterinary medical oncology became a sub-specialty of the Euro-
pean College of Veterinary Medicine (ECVIM-CA) in 2004 and
now boasts 58 diplomats and 15 approved training centres. This
evolving veterinary community has been responsible for numer-
ous research programmes from basic molecular science through
to clinical trials and generated the knowledge and experience
that underpins our current clinical practice (Fig 1). Furthermore,
international collaborations such as that between the executive
committees of VCS and ESVONC to lead exchange of ideas
and research at annual conferences, and networks such as the
Veterinary Cooperative Oncology Group, Veterinary Radiation
Therapy Oncology Group, Veterinary Society of Surgical Oncol-
ogy have worked collectively to establish guidelines for the best
practice of Veterinary Oncology in its widest sense.
The first part of this review will consider the developments and
advances in different specialties that contribute to modern veteri-
nary oncology. In the second part, common canine tumours: soft
tissue sarcoma, mast cell tumour (MCT) and lymphoma will be
used as examples of how advances in understanding, diagnosis
and management of these conditions have led to current treat-
ment recommendations.
Pathology & clinical pathology
At the start of the discussion to his 1959 paper Earnest Cotchin
stated:
“. … a careful study by histopathological and other methods
of large numbers of tumour cases of different kinds will help
to define their range of biological behaviour, so that not only
 Veterinary oncology 60 years
will soundly-based diagnosis and prognosis be available to
the clinician, but information will accumulate which will form
a valid key to the interpretation of therapeutic trials….”
Within 24 months (1961), the University of California Press
published the first edition of “Tumours of Domestic Animals”
edited by Moulton (1961); this textbook is now in its fifth edi-
tion and edited by Donald J Meuten, and regarded as the most
comprehensive and authoritative of references on veterinary
tumour pathology in common domestic animals. The compari-
son between these two texts demonstrates clearly how far our
knowledge and understanding of the pathology of tumours has
developed during this period of time. Expanded beyond basic
morphological interpretation of haematoxylin and eosin-stained
tumour sections, to histochemical staining, immuno-labelling
and further to molecular subtyping by techniques such as in situ
hybridisation and polymerase chain reaction (PCR).
H&E-stained sections remain the first line approach to histo-
logical diagnosis for most tumours, and it is through studies in
the 1980s by pathologists such as Bostock working at Cambridge
and Patnaik at the Animal Medical Centre in New York that we
now rely not only on histological diagnosis of tumour type but
also the grade to guide prognosis. Histological grading is based
on features such as degree of tumour differentiation, cellularity,
cellular pleomorphism, amount of stroma, vascularity, mitotic
activity, tumour necrosis, inflammatory infiltrate and invasion
of adjacent tissues (Bostock 1973, Patnaik et al. 1984, Dennis
et al. 2011). These features may be used to predict the likely bio-
logical behaviour. A high-grade tumour of any histological type
will typically carry a higher risk of metastasis than its low grade
counterpart.
H&E diagnosis relies on the pathologist being able to recog-
nise the likely histogenesis of the tumour cells by their micro-
scopic features, such as nuclear shape and appearance, amount
and granularity of cytoplasm and associated stoma. In many
tumours, cells are poorly differentiated and a major stromal
component is lacking. These may be referred to as “poorly dif-
ferentiated” or “anaplastic” tumours and in some cases even the
likely tissue origin, for example, epithelial, mesenchymal, mela-
nocytic or lymphoid, may not be apparent. Histochemical stains
or dyes such as methyl green, toluidine blue, periodic acid-Shiff
were originally used to try to determine the cell of origin in such
cases. In 1975, the first monoclonal antibodies were raised using
a hybridoma technique in mice (Koher & Milstein 1975). Spe-
cific antibodies, conjugated with fluorochrome-labelled second-
ary antibodies can be applied to tissue sections to identify specific
cell-surface antigens associated with different tissue types. Immu-
nohistochemistry may also provide an important aid to prog-
nostication. For example, Ki67 is a large nuclear protein that is
expressed exclusively by cells in all phases of the cell cycle except
G0, and so if a cell is expressing Ki67, it is replicating. It is an
independent prognostic factor in many human tumours, and it
has been shown to be an independent prognostic factor in canine
MCTs (Scase et al. 2006).
There are an ever-increasing range of immunohistochemical
labelling techniques that can be used in canine and feline tissue
Journal of Small Animal Practice • © 2019 British Small Animal Veterinary Association 3
(as demonstrated by Case 1) and research continues to use these
techniques to sub-classify tumours which were previously indistin-
guishable from each other. Today, veterinary oncologists make use
of this information to provide more accurate prognostic predictions
and tailor treatment plans. In addition, it is likely that application
of these techniques will help to identify new therapeutic targets,
that will further increase the arsenal of drugs and other agents, such
as antibodies and small molecule kinase inhibitors, that might be
rationally applied to veterinary cancer patients in future.
Effective communication between pathologist and clinician
is crucial to the successful management of any cancer patient.
Through an initiative of the American College of Veterinary
Pathologists’ Oncology Committee a standardised approach
to tumour biopsies has been established that provides recom-
mended guidelines for sample submission, tissue trimming, mar-
gin evaluation and reporting (Kamstock et al. 2011). Whilst not
mandatory, these guidelines have been reviewed and endorsed by
the World Small Animal Veterinary Association as an effective
means of assisting the primary veterinarian, veterinary oncolo-
gist and veterinary pathologist to optimising management of the
veterinary cancer patient.
Although a histological diagnosis provides the most secure,
definitive diagnosis of tumour type and grade, cytological exami-
nation of tumour cells harvested from effusions, other body
fluids or from fine needle aspiration from a lesion can provide
important information about the nature of a lesion in a less inva-
sive and time and cost effective manner. Cytology may differenti-
ate inflammatory from neoplastic lesions and, in the case of the
latter, indicate possible cell type. Whilst some tumours may have
characteristic cytological features (e.g. MCT), cytology alone
should not be relied upon to provide a definitive diagnosis for
many tumour types, neither can it be used for grading. However,
when combined with immunophenotyping techniques such as
flow cytometry, it can be a powerful diagnostic tool, especially in
lymphoid tumours and leukaemias (Case 2). Recently it has been
shown that the expression of certain flow cytometry markers has
prognostic significance in canine lymphoma, particularly T cell
lymphoma, potentially allowing better prognostication for indi-
vidual patients (Avery et al, 2014, Deravi et al, 2017), However,
there is still much to learn about the use and application of these
markers in veterinary oncology.
 J. M. Dobson
Molecular diagnostics: PCR for antigen receptor
rearrangements
Lymphoid cells normally contain DNA antigen binding regions
(encoded by specific DNA sequences) that are unique. Clonal-
ity testing uses the PCR to detect and amplify antigen receptor
genes in order to establish whether populations of lymphoid cells
are clonal (with the same receptor rearrangement) or polyclonal.
Based on the belief that malignancies are clonal, a clonal rear-
rangement indicates the likelihood of neoplasia, as indicated by
Case 3 (and see Keller et al. 2016).
Biochemical markers of neoplastic disease
In general, veterinary oncology still lacks effective cancer screen-
ing blood tests such as the prostate-specific antigen test available
for human patients (Tilki et al. 2015). Thymidine kinase type 1
(TK1), C-reactive protein and haptoglobin are elevated in serum
of dogs with lymphoproliferative disease (Mischke et al. 2007,
Selting et al, 2016) and TK1, in particular, may be useful for
monitoring therapeutic response in canine lymphoma (Von Euler
et al. 2009). The acute phase protein, C-reactive protein, appears
elevated in other neoplastic conditions such as canine mammary
carcinoma (Planellas et al. 2009, Selting et al. 2016) and histio-
cytic sarcoma (personal observation) probably reflecting a role
for inflammation in these tumour types. Serum ferritin has also
been proposed as a tumour marker for canine histiocytic sarcoma
(Friedrichs et al. 2010). Yet, to date, none of these markers are
used routinely in veterinary oncological practice.
Recent advances in molecular oncology resulted in the dis-
covery of the BRAF V595E mutation in around 80% of canine
urothelial carcinomas. This has allowed the development of a
commercially available test (the Cadet BRAF mutation detection
4 Journal of Small Animal Practice • © 2019 British Small Animal Veterinary Association
essay) to detect urothelial bladder cancer, so avoiding more inva-
sive procedures to achieve a definitive diagnosis. This test uses a
droplet digital PCR assay to detect the mutation in urine of dogs
with urothelial carcinoma. The sensitivity and specificity of the
test is 80% and 100% respectively (Mochizuki et al. 2015). The
limitations of this test are the possible lack of expression of the
BRAF mutation in 20% of urothelial carcinomas (resulting in
false negatives) and, less commonly, the presence of a different
type of tumour in the bladder or prostate.
Diagnostic imaging
In the 1960s, Owen had to rely on radiography to aid diagno-
sis and clinically “stage” his patients. The intervening years have
seen huge developments in imaging modalities routinely used in
veterinary practice, first ultrasound, which allowed the structure
of abdominal viscera to be seen in more detail and, more recently,
cross sectional imaging by CT and MRI.
Nowadays, modern diagnostic imaging plays a crucial role in
the assessment of the cancer patient, in some cases assisting in
detection and diagnosis of neoplasia and, in all cases of malignant
tumours, in assessment of metastatic disease and hence the clini-
cal stage, of a tumour at a set point in time.
CT is more sensitive than radiography for detecting pulmo-
nary nodules and is becoming the imaging method of choice for
assessment of pulmonary metastasis, especially for highly malig-
nant tumours such as osteosarcoma and melanoma (Armbrust
et al. 2012); in oral malignant melanoma, CT can also be used to
assess mandibular and retropharyngeal lymphadenopathy. How-
ever, even with contrast enhancement, the sensitivity of CT in
detection of cervical lymph node metastasis is low and CT can-
not be relied on alone for this purpose (Skinner et al. 2018). On
the other hand, CT is more sensitive than radiography for detec-
tion of mediastinal lymphadenopathy and would be the method
of choice for assessment of an animal with a lung mass. CT can
also provide good soft tissue definition of abdominal (mesenteric
or medial iliac and hypogastric) lymph nodes and can be used to
assess intrapelvic sacral lymph nodes if these are not accessible by
ultrasound. Contrast-enhanced CT can highlight important dif-
ferences in imaging characteristics between benign and malignant
splenic lesions but, as with other imaging techniques, it does not
provide a histological or cytological diagnosis (Fife et al, 2004).
Finally, CT may also be more sensitive in detecting bony
metastases and is used for this purpose (amongst others) com-
bined with positron emission tomography in human cancer
patients (Park et al. 2018).
In contrast to CT, MRI provides excellent soft tissue detail
and anatomic definition due to its superior greyscale image con-
trast, but provides little detail of cortical bone. It is particularly
sensitive for imaging the brain and spinal cord. MRI is also very
useful for pretreatment assessment of soft tissue sarcomas and in
the evaluation of intranasal tumours which often extend into the
retrobulbar space, or through the cribriform plate into the frontal
region of the brain. Meningeal hyperintensity of the olfactory
bulbs and tumour extension into the caudal nasal recess are quite
common features of intranasal tumours in dogs (Agthe et al.
2009). MRI can be used for imaging primary tumours of the
 Veterinary oncology 60 years
head and neck, spine, dorsum and pelvis but, because of the need
for the area of interest to be motionless during acquisition of
images, it is used less frequently for imaging lesions of the chest
and abdomen in small animals. Gating systems can be applied to
negate movement artefact but, because gating is complicated and
time-consuming to apply, CT is preferable for imaging tumours
of these regions. Although whole body MRI is used in staging
human cancer patients, its role in veterinary medicine is more
directed at staging the primary tumour than assessing the patient
for metastases. Arguably the most important impact of MRI in
veterinary oncology has been in detection and diagnosis of intra-
cranial tumours. Although the gold standard for diagnosis is his-
topathological examination of a tumour biopsy their site implies
that biopsy of many intracranial tumours carries a high risk of
morbidity and the procedure itself can be costly. In the absence
of biopsy, MRI can be a sensitive and reasonably specific alterna-
tive for diagnosis of intracranial neoplasia (Wisner et al. 2011).
Treatment of cancer
In April 1972, BSAVA hosted a symposium on “The treatment
of malignant neoplasms” at its 15th Annual Congress in Lon-
don and papers subsequently published in JSAP by Silver 1972,
Bostock & Owen 1972 and Baker (1972) described the use of
radiotherapy for the treatment of neoplasia, chemotherapy of
canine and feline neoplasia and surgical management respec-
tively. However, although the basic principles underpinning
the use of these modalities was understood, all concluded that
the veterinary literature at that time was deficient in follow-up
surveys documenting response to treatment and outcomes and
called for clinical research to establish the efficacy of these treat-
ment in small animal oncology. The veterinary oncology com-
munity has responded to this challenge and numerous clinical
studies documenting a plethora of treatments for many tumour
types may now be found in the literature. Unfortunately the
majority of these studies are small, retrospective case series and
robust evidence of efficacy from large scale controlled clini-
cal trials, which forms the basis for standard of care in human
medicine, is still sorely lacking in the veterinary field. Hence, we
still do not have or know the solution to many of the neoplastic
conundrums that present on a daily basis in small animal prac-
tice. A recent article published in JSAP reviewed the develop-
ment of veterinary radiotherapy and some of the controversies
that still exist about how best to deliver and apply radiotherapy
in veterinary oncology (Nolan & Dobson 2018). Well designed
and conducted stage-stratified and randomised clinical trials are
still needed to address the many outstanding questions regarding
how best to manage a particular neoplasm and to provide a secure
evidence base, particularly for the use of chemotherapy in small
animal practice. However, although in many cases the evidence
base is weak, certain “standards of care” have been established
for selected tumours. A detailed review of the development of
veterinary surgical oncology, chemotherapy and radiotherapy is
beyond the scope of this article. The following discussion of how
the management of specific tumour types has evolved over time
is the means chosen here to review the development these treat-
ment modalities and demonstrate how their application in man-
Journal of Small Animal Practice • © 2019 British Small Animal Veterinary Association 5
agement of clinical cases has led to the development of veterinary
oncology as a multidisciplinary speciality.
Example 1: Soft tissue sarcoma
In contrast to humans, in which soft tissue sarcomas are rare, repre-
senting 1% of all malignancies, they are relatively common tumours
in cats and dogs, in which they represent 10 to 20% of all neo-
plasms (Dobson et al. 2002). Although soft tissue sarcomas may
arise at many sites, the majority in dogs and cats affect the skin, sub-
cutis or deeper connective tissues, and most of the following discus-
sion is focused on tumours at these more common sites. There are
many articles that document histological features and classification
schemes for soft tissue sarcomas and this has changed and improved
over the years as a result of advances in histological and immuno-
histochemistry techniques (Dennis et al. 2011, Hohenhaus et al,
2016). For example, the term “malignant fibrous histiocytoma” was
historically used to describe a group of pleomorphic sarcomas of
different origins containing mixtures of round, spindle and multi-
nucleated giant cells (Kerlin & Hendrick 1996) that are now largely
classified as part of the histiocytic sarcoma complex, whose myeloid
dendritic origin is demonstrated by expression of CD1, CD11c,
MHC class II and ICAM-1, and more recently CD18 and Iba-1
(Affolter & Moore 2002, Pierezan et al. 2014).
Soft tissue sarcomas are still often considered as a group
because, although there are a number of distinct histological
types, they share common biological behaviour, and it is the
grade of the tumour that dictates its likely metastatic potential
(Dennis et al. 2011). Due to their infiltrating pattern of growth,
local recurrence is generally a more common cause of treatment
failure than development of metastasis. Most soft tissue sarcomas
are low to intermediate in grade and are traditionally refractory
to treatment with chemotherapy or radiotherapy, and so surgi-
cal management is key to success. The surgical approach to soft
tissue sarcomas has evolved considerably over the past 60 years.
Recognising that local recurrence was the result of a failure to
surgically remove all tumour cells, surgeons in the 1990s became
more and more aggressive in their approach to these tumours,
and developed techniques to reconstruct the large tissue defi-
cits that resulted (Dernell et al. 1998). As a result, the standard
recommendation for resection of a soft tissue sarcoma “en bloc”
was a minimum of 3 cm of normal tissue laterally and one fascial
plane deep to the tumour (Kuntz et al. 1997, Dernell et al. 1998,
Ehrhart 2005). However, recent evidence does not support the
need for compartmental, or even wide resection in every case,
indeed several reports have shown that good outcomes can be
achieved by primary care practitioners despite narrow surgical
excision margins (Chase et al. 2009, Bray et al. 2014, Hohen-
haus et al. 2016). Unfortunately, there are currently no diagnos-
tic tests that can reliably predict the surgical margin required for
complete excision of a specific tumour. CT or MRI may allow
the surgeon to determine preoperatively whether the tumour is
anatomically confined to clear tissue boundaries or has spread
into ill-defined fascial planes and spaces (Kraun et al. 2015) and
contrast media may be used to enhance the distinction between
tumour and surrounding tissues. The evaluation of the periph-
eral tumour growth pattern on preoperative MRI sequences in
 J. M. Dobson

human patients has identified different growth patterns which
are known to be of prognostic significance, in particular an infil-
trative growth pattern signifies a poor prognosis compared to a to
a “pushing” pattern of growth (Fernebro et al. 2006).
Current recommendations for surgical management of soft
tissue sarcoma still suggest a 2 to 3 cm lateral margin where pos-
sible and one clear deep fascial plane (Prpich et al. 2013). For
lesions on the distal limb these margins are rarely achievable and
an alternative strategy is a planned cytoreductive surgery fol-
lowed postoperatively by radiotherapy (Fig  2). It is still debat-
able how best to deliver the radiation in terms of fractionation:
a 5-year survival rate of 76% with median disease-free survival
of 1082 days was achieved in 38 dogs receiving 3 Gy fractions,
given every other day using cobalt-60, for a total of 63 Gy in
one report (McKnight et al. 2000) compared to a 5-year survival
rate of 65% for 56 dogs treated with once weekly fractions of 8
to 9 Gy to a total of 32 to 36Gy using a 4MV linear accelerator
(Demetriou et al. 2012); median survival was not reached in this
study (Fig 3). A recent two-part review contains a more compre-
hensive update on the current understanding and management
of canine soft tissue sarcoma (Bray 2016a, 2016b).
Another development in veterinary oncology in the past
60 years is the emergence of feline injection site sarcoma (FISS),
first reported in the 1990’s (Hendrick et al. 1992). These are rec-
ognised as a heterogenous group of sarcomas that occur at injec-
tion sites in cats months to years following injection/vaccination
and are a good example of how collaboration between clinicians
and pathologists has helped us to identify this condition. FISS
can be defined as those tumours that develop in an area used
for injections (traditionally the scruff or interscapular area in the
case of vaccinations), have characteristic histological features,
display aggressive growth patterns and tend to recur. The link
between vaccination and sarcoma formation was first suggested
in 1991, following the introduction of Pennsylvania State laws
making vaccination of cats against rabies compulsory. The causal
and temporal relationship between vaccination and sarcoma
formation has been supported by a shift in the distribution of
sarcomas subsequent to the Vaccine-Associated Feline Sarcoma

FIG 2. Marginal excision of recurrent soft tissue sarcoma. (A) Recurrent soft tissue sarcoma affecting the caudal aspect of elbow. (B) Limb prepared
for surgery with marginal excision inked. (C) Recurrent tumour excised with remaining wound

6 Journal of Small Animal Practice • © 2019 British Small Animal Veterinary Association

1 rently offered by several commercial laboratories: these include
.8
Cumulative Survival
.6
.4
.2
0 Warland et al. 2014 (2)).
0 250 500 750 1000 1250 1500
Time (days)
FIG 3. Kaplan–Meier product-limit plot of local recurrence for 56 dogs
with limb sarcoma treated by intentional marginal excision followed by
radiotherapy, showing censored individuals (Demetriou et al. 2012)
Task Force recommendation for differential vaccination sites in
the pelvic limbs and right shoulder area (Romatowski 1997).
Radical first surgery is likely to be the most important prognostic
factor, although both pre and postoperative radiotherapy, che-
motherapy and toceranib have been reported to be useful in the
management of FISS (Ladlow 2013 – review) and Oncept-Il2
(Merial/Boehringer) a feline interleukin 2 recombinant canary
pox virus, has been licensed in Europe for adjunctive treatment
of FISS in combination with surgical resection and radiotherapy
(Jourdier et al. 2003). To date, the use of this product has not
been widely reported.
Example 2: Canine MCTs
As Ernest Cotchin observed in the 1960s, MCTs are common
in dogs. They mainly affect the skin and subcutis, although vis-
ceral forms of the disease are recognised. Canine MCTs present a
clinical challenge because of their variable behaviour; the majority
follow a reasonably benign course but a small proportion is
aggressive and metastatic. The management of canine MCTs has
improved over the years, guided by an increased understanding of
their pathology and biological behaviour. In the late 1970’s/early
1980’s both Patnaik and Bostock developed histological grading
schemes to predict prognosis (Bostock 1973, Patnaik et al. 1984).
The more widely-adopted Patnaik system divided tumours into
three tiers, with grade 1 being largely benign (<10% metastasise),
grade 3 being highly malignant (>80% metastasise) and grade 2
tumours being difficult to predict, with most behaving in a benign
manner, but a sizeable minority behaving aggressively (5 to 25%
metastasise). The increasing frequency of diagnosis of grade 2
MCTs and continuing uncertainty surrounding prognosis led a
large group of veterinary pathologists to review the grading sys-
tems. In 2011, a new grading system was published by Kiupel
et al. (2011) which aimed to eliminate the intermediate tier by
classifying all tumours as either high or low grade. In order to
allow better repeatability between pathologists, the Kiupel grading
system uses more objective numbers of certain cellular features in
order to classify the tumour as being of a high grade. This grading
system has proved popular, largely due to the simplicity provided
by the loss of the challenging intermediate grade tumours.
A number of proliferation markers have been investigated to
aid prognostication for intermediate grade tumours and are cur-
Journal of Small Animal Practice • © 2019 British Small Animal Veterinary Association 7
Veterinary oncology 60 years
mitotic index (MI), Ki67, c-kit mutation status and KIT staining
pattern, AgNORs and proliferating cell nuclear antigen (PCNA).
MI, the number of mitoses in 10 high power fields (hpf ) is a
strong prognostic indicator but the literature is inconsistent
about the best cut-off to use for predicting survival, with reported
values of 5 and 7 per 10hpfs, although other data suggest a cut
off of 2 per 10 hpf (Patnaik et al. 1984 (5), Kiupel et al, 2011 (7)
1750 2000 2250 Ki67 protein expression is used as an indirect marker of cel-
lular proliferation. Scase et al. (2006) reported using a cut-off of
1.8% Ki67+ cells predicted survival, independently of tumour
grade. One-, 2- and 3-year survival rates were 92, 86 and 77%
for low Ki67 and 43, 21 and 21% for high Ki67. Many labora-
tories now report Ki67 as an extra immunohistochemistry test,
although some confusion arises because different laboratories
report different methods for quantifying and reporting Ki67.
Furthermore, Ki67 and MI results may be discordant, creating
further challenges (Van Lelyveld et al. 2015).
MCTs metastasise to draining lymph nodes, liver, spleen (and
bone marrow) and can also give rise to cutaneous metastases.
Clinical staging of MCTs can now be directed by a knowledge
of their pattern of metastasis because the status of the local /
regional lymph node has been shown to be crucial. In a study of
220 dogs with MCTs, 30.9% had nodal metastasis at presenta-
tion and 6.8% also had distant metastasis. The local lymph node
was sentinel to metastasis and, in the absence of lymph node
metastasis, the utility of further staging was low (Warland et al.
2014). However, in some tumours and sites the predicted lym-
phatic drainage is not clinically evident and some oncologists still
advocate abdominal ultrasound and FNAs of liver and spleen in
all dogs with MCTs, plus bone marrow evaluation in high-risk
patients (Aubry et al. 2014).
Controversy still reigns about the cytological interpretation of
FNA samples, especially those obtained from the draining lymph
node, because up to 24% of normal dogs will have a low number
of morphologically normal mast cells identified on cytology in
a lymph node (Bookbinder et al. 1992). If mast cells appear in
clusters or sheets this is more indicative of metastasis, although
even histological assessment of excised lymph nodes can be
equivocal, with some studies suggesting lymph node metastasis is
of prognostic significance and others that it is not (Dobson et al.
2004, Krick et al. 2009). Recently a histological scoring system
has been proposed for classification of nodal metastases with cat-
egories of HN0 – HN3 indicating levels of certainty of metastasis
(Weishaar et al. 2014),
Whenever possible, surgery should be considered the treat-
ment of choice for MCT and the surgical approach and indica-
tions for adjuvant radiotherapy are similar to those discussed for
soft tissue sarcomas. The use of cytotoxic drugs in the treatment
of MCTs remains controversial. Empirical clinical evidence sug-
gests that some MCTs regress in response to high dose prednis-
olone treatment alone, although this response is rarely durable
(McCaw et al. 1994). Vinblastine, in combination with predniso-
lone, and chlorambucil with prednisolone have been shown to be
beneficial in the management of high grade MCTs (Dobson et al.
 J. M. Dobson
2004, Hayes et al. 2007). Use of lomustine has also been reported
(Rassnick et al. 1999). No protocol has been shown to be more
successful than another, with overall response rates around 40 to
50%; randomised controlled clinical trials are lacking.
Traditional cytotoxic drugs are no longer the only option for
treatment of high grade or inoperable MCTs. Tyrosine kinases
are a diverse family of proteins involved in cell signalling path-
ways. They regulate key cellular functions such as proliferation,
differentiation, migration, activation and survival. Over recent
years, abnormalities of tyrosine kinase function, such as muta-
tions or overexpression, have been demonstrated in many human
and veterinary cancers (London 2004 – review). In canine MCTs,
mutations in the c-kit gene affect 30 to 40% of tumours, with a
higher prevalence in higher grade tumours (Webster et al. 2006,
Gil da Costa 2015).
Masitinib (Masivet) and toceranib phosphate (Palladia) are
tyrosine kinase inhibitors licensed for use in dogs with unresect-
able, grade II & III MCT. Both drugs have demonstrated efficacy
as single agents in prospective clinical trials in dogs (Hahn et al.
2008, London et al. 2009). Recently, dogs with MCTs treated with
masitinib showed around a 50% response rate and a median sur-
vival time (MST) of 630 days in those patients that responded to
masitinib therapy compared to 137 days for those which did not
respond (Smrkovski et al. 2013). The most common adverse effects
were haematological and gastrointestinal, followed by protein-los-
ing nephropathy. There is emerging evidence that masitinib may
be more effective in less aggressive tumours (Miller et al. 2016).
In 2012, following several meetings of European Veterinary
Oncologists and other interested parties, a European Consensus
document on MCTs in dogs and cats was published (Blackwood
et al. 2012) Largely based on internationally published studies
with a strong emphasis on evidence base, the aim of this docu-
ment was to form the basis of our understanding of this disease
at the current time.
Canine lymphoma
Lymphoma (malignant lymphoma) is a common neoplastic
condition in the dog which has received considerable veteri-
nary interest because it is one of the more treatable “cancers”
in small animal medicine. Since 1973, when it was first shown
that prednisolone, cyclophosphamide and vincristine could be
used to treat canine lymphoma (Squire et al. 1973), numerous
publications have documented the response of this disease to a
variety of chemotherapeutic protocols, including single agents
such as doxorubicin, simple combination protocols comprising
cyclophosphamide, vincristine and prednisolone and the more
dose-intense combinations including agents such as doxorubicin
and L-asparaginase (Madewell 1975, MacEwen et al. 1981, Cot-
ter 1983, Carter et al. 1987, Postorino et al. 1989, Keller et al.
1993, Dobson & Gorman 1994). All these publications docu-
ment remission rates in the order of 75 to 90% with mean or
MSTs ranging from 6 to 15 months; empirical evidence suggests
that the more dose-intense protocols containing doxorubicin may
provide a better response but, yet again, randomised, controlled
clinical trials are lacking. Furthermore, these “conventional” che-
motherapy protocols appear to have “hit a ceiling of response” so
8 Journal of Small Animal Practice • © 2019 British Small Animal Veterinary Association
that use of additional or different cytotoxic drugs does not appear
to improve survival times.
In most of these clinical case series canine multicentric lym-
phoma was considered a single disease entity but, within each
series of affected animals, there is considerable variation in
response with some tumours showing a rapid and sustained
response whilst others relapse and become resistant to therapy
within a short space of time and some do not respond at all. This
suggests that there are different subtypes of lymphoma with dif-
ferent biological behaviours and responses to treatment.
Some of the first monoclonal antibodies to be developed and
used in the dog were to identify different lymphocyte lineages
(Moore et al. 1992). As a result, the immunophenotype of lym-
phoma was shown to be an important prognostic indicator with B
cell tumours having a better prognosis than T cell tumours (Dob-
son et al. 2001). However, since 60% of canine lymphoma are B
cell and there is still considerable variation in tumour response and
survival within this group, knowledge of B or T cell type alone
does not provide the clinician with a definitive prognosis upon
which to base recommendations for therapy (Ponce et al. 2004).
Many attempts have been made to classify canine lymphoma
according to histological criteria, but a clinically-relevant classi-
fication system for this disease has yet to be universally accepted.
Although the NCI working formulation was favoured by some
pathologists, the Kiel classification appeared to be the most
appropriate system for canine malignant lymphoma because it
put little emphasis on architecture, which is almost always diffuse
in the dog and it allowed greater subdivision of the high grade
lymphomas (Greenlee et al. 1990, Teske et al. 1994). The WHO
Classification of haematopoietic tumours of domestic animals
was recently updated (Valli et al. 2002) and now provides a com-
prehensive classification, subdivided by immunophenotype and
mirroring the WHO classification of human haematopoietic
tumours. However, the prognostic value of this classification has
not been validated, neither has it been widely adopted by com-
mercial veterinary pathology laboratories in the UK. A French
group used an updated Kiel classification to provide a clinically-
relevant classification of canine lymphoma (Fournel-Fleury et al.
1997) and, using this morphological classification in 57 clini-
cal, cases they were able to identify subsets of canine lymphoma
that correlated not only with clinical presentation but also with
response to treatment and prognosis (Ponce et al. 2004). More
recently this group identified high- and low-grade T cell and B
cell lymphomas and subsets within each of these groups as having
different presentations and treatment response (Ponce et al. 2010 –
Table  1). Comazzi & Gelain (2011) used flow cytometry to
refine the cytological diagnosis of canine lymphoma - and
molecular profiling has also been used to reveal subtypes of
canine lymphoma that carry different prognoses (Frantz et al.
2013). The result of all these studies is that we now understand
that canine lymphoma is not one disease entity but that there
are many (probably greater than 20) subtypes that differ in their
clinical behaviour and therapeutic response. Some subtypes are
well defined and some less so at present. Whilst some subtypes
may be diagnosed by flow cytometry, histopathology is necessary
for those subtypes requiring a structural evaluation of nodal or
 Veterinary oncology 60 years

Table 1. Classification of canine lymphoma (Ponce et al. Future directions

2010) This review has addressed advances in veterinary oncology over
B cell lymphoma the past 60 years that have moulded our current clinical practice.
Low-grade B cell lymphoma (n=81) High-grade B cell lymphoma (n=307) Looking forward there are some exciting developments in inter-
Small lymphocytic aspect (n=2) Centroblastic monomorphic
(n=4)
ventional oncology and immunotherapy that are likely to impact
Prolymphocytic aspect (n=1) Centroblastic polymorphic veterinary clinic practice in the next 10 to 15 years, indeed some,
(n=234) such as the canine melanoma vaccine (Oncept – Merial) is
Marginal zone (n=66) Immunoblastic (n=47)
Centroblastic/centrocytic (n=3) Anaplastic/mediastinal (n=1)
already available for veterinary use. The potential for modula-
Burkitt type (n=10) tion of the immune system through biological response modi-
Plasmacytoid (n=6) fiers (e.g. cytokines), immunogene therapy, cancer vaccines,
T cell lymphoma
Precursor T cell – lymphoblastic (n=17)
immune cell-based immunotherapy and monoclonal antibod-
Mature T cell (n=126) ies was recently reviewed by Killick et al. (2015). In the last
Low grade (n=26) High grade (n=100) 30 years, interventional oncology has become common practice
Small clear cell/T zone (n=20) Pleomorphic mixed (n=39) in human medicine, offering an alternative or, in some cases,
Prolymphocytic (n=1) Pleomorphic large cell (n=13)
Pleomorphic small cell (n=5) Immunoblastic (n=7) a complementary treatment option for some human cancers.
Plasmacytoid (n=19) The last few years have seen an increase in interventional oncol-
Aggressive large granular cell ogy procedures performed in pets. Stenting techniques have
(n=1)
been used with success in dogs to relieve malignant obstruc-
tion of the urethra (Blackburn et al. 2013). More recently, simi-
splenic architecture, so there is a strong case for lymphadenec- lar techniques have been applied in malignant obstruction in
tomy to confirm and better characterise a cytological diagnosis the ureters, oesophagus, colon and major vessels (Hume et al.
(Sayag et al. 2018). There is no consensus between Europe and 2006, Schlicksup et al. 2009, Berent et al. 2011). Intraarterial
the USA on classification of canine lymphoma but a prognosti- chemotherapy, trans-arterial embolisation and chemoembolisa-
cally-relevant theme appears to be developing with three main tion all use an arterial access (femoral or carotid artery) to insert
groups (excluding certain site specific subtypes such as primary catheters and guide wires that are fluoroscopically guided to
splenic lymphoma): the tumour feeding artery, so to deliver chemotherapy and/or
embolic agents directly to the tumour.
• Diffuse large cell B cell lymphoma (DLBCL) – the most com- Radiofrequency ablation and microwave ablation are prob-
mon form in the dog ably the most widely used minimally-invasive techniques in
• High grade, lymphoblastic peripheral T cell lymphoma – gen- human medicine. Both techniques use heat generated by a
erally carry a poor prognosis magnetic field and electric current respectively, both causing
• Low-grade, small-cell T cell (T – zone) lymphomas – more coagulative necrosis. These methods been rarely used in veteri-
indolent behaviour and tend to show the longest survival. nary medicine to treat primary hyperparathyroidism and only
two case reports assessed the efficacy of microwave ablation in
As there is some evidence that T cell lymphomas may be small metastatic tumours of the liver and lungs (Pollard et al.
more responsive to lomustine and less responsive to doxorubicin, 2001, Mazzaccari et al. 2017, Yang et al. 2017). Unfortunately
many veterinary oncologists are now treating the high grade B both radiofrequency ablation and microwave ablation can be
and T cell lymphomas differently, tending to use doxorubicin- used only on small tumours – usually less than 3 cm – limiting
based protocols (e.g. CHOP) for DLBCL and lomustine-based their use in more advanced diseases. Although interventional
protocols (LOP or LOPP) for treatment of high grade T cell oncology is still in his infancy in veterinary medicine, it is likely
lymphoma, although no randomised clinical studies have been that with rapidly growing knowledge, skills and collaboration
conducted to support this approach (Brown et al. 2018, Morgan between different veterinary specialists, it will become standard
et al. 2018). Chlorambucil shows some utility for the treatment practice for the treatment of many neoplastic diseases in the
of low-grade, small cell T cell, intestinal lymphoma (Lane et al. near future.
2018). The reader is referred to some recent review articles for a In conclusion, although veterinary oncology has come a long
more detailed consideration on current approach to management way in the past 60 years, there are still large deficits in our knowl-
of canine lymphoma (Marcanato 2011, Marconato et al. 2017). edge and understanding of neoplasia in companion animals and
As can be appreciated, the diagnostic and therapeutic the evidence base for many of the currently used diagnostic and
approach to canine lymphoma is currently poorly standardised, therapeutic approaches is weak. The veterinary oncology com-
with large variations between institutions. In 2015, a European munity should be moving to address many of these outstanding
Canine Lymphoma Network was established as an initiative to questions through well-constructed, large-scale, multicentre, col-
generate consensus guidelines for diagnosis and therapy in canine laborative clinical research programmes. The huge advances in
lymphoma (Comazzi et al. 2015). Further collaborative work is human cancer therapy through targeted therapies such as anti-
still required to standardise the clinical approach to canine lym- bodies and small molecule kinase inhibitors and the application
phoma and thus guide and inform clinical research and decision of molecular analysis of individual tumours are already leading
making in this area for the future. to a more tailored, patient/tumour specific approach to cancer

Journal of Small Animal Practice • © 2019 British Small Animal Veterinary Association 9
 J. M. Dobson
therapy, so these are exciting times and we need to work together
to realise similar opportunities for our veterinary cancer patients.
Acknowledgements
The author wishes to acknowledge the valuable contributions
of colleagues: Antonio Giuliano (Interventional Oncology) Fer-
nando Constantino-Casas (sections for Case 1), Cassia Hare and
Sabine Hammer for contributions to Cases 2 & 3 and related text.
Conflict of interest
The author has no conflict of interest.
References
Avery, P. R., Burton, J., Bromberek, J. L., et al. (2014) Flow cytometric characteriza-
tion and clinical outcome of CD4+ T-cell lymphoma in dogs: 67 cases. Journal
of Veterinary Internal Medicine 58, 538-46
Adams, V. J., Evans, K. M., Sampson, J., et al. (2010) Methods and mortality
results of a health survey of purebred dogs in the UK. Journal of Small Animal
Practice 51, 512-524
Affolter, V. K. & Moore, P. F. (2002) Localized and disseminated histiocytic sarcoma
of dendritic cell origin in dogs. Veterinary Pathology 39, 74-83
Agthe, P., Caine, A. R., Gear, R. N., et al. (2009) Prognostic significance of specific
magnetic resonance imaging features in canine nasal tumours treated by radio-
therapy. Journal of Small Animal Practice 50, 641-648
Armbrust, L. J., Biller, D., Bamford, A., et al. (2012) Comparison of three-view tho-
racic radiography and tomography for detection of pulmonary nodules in dogs
with neoplasia. JAVMA 240, 1088-1094
Aubry, O. A., Spangler, E. A., Scheis, S. E., et al. (2014) Evaluation of bone mar-
row aspirates from multiple sites for staging canine lymphoma and mast cell
tumours. Veterinary & Comparative Oncology 12, 58-66
Baker, G. J. (1972) Treatment if malignant neoplasia. Surgical Management. Jour-
nal of Small Animal Practice 13, 373-379
Berent, C. W., Beal, M., Brown, D. C., et al. (2011) Use of indwelling, double-
pigtail stents for treatment of malignant ureteral obstruction in dogs: 12 cases
(2006-2009). Journal of the American Veterinary Medical Association 238,
1017-1025
Blackburn, A. L., Berent, A. C., Weisse, C. W., et al. (2013) Brown Evaluation of
outcome following urethral stent placement for the treatment of obstructive car-
cinoma of the urethra in dogs: 42 cases (2004-2008). Journal of the American
Veterinary Medical Association 242, 59-68
Blackwood, L., Murphy, S., Buracco, P., et al. (2012) European consensus docu-
ment on mast cell tumours in dogs and cats. Veterinary and Comparative Oncol-
ogy 10, e1-e29
Bonnett, B. N. & Egenvall, A. (2010) Age patterns of disease and death in insured
Swedish dogs. Cats and Horses. Journal of Comparative Pathology 142:S33, S38
Bonnett, B. N., Egenvall, A., Olson, P., et al. (1997) Mortality in insured Swedish
dogs: rates and causes of death in various breeds. Veterinary Record 141, 40-44
Bookbinder, P. F., Butt, M. T. & Harvey, H. J. (1992) Determination of the number of
mast cells in lymph node, bone marrow and buffy coat cytological specimens in
dogs. Journal of the American Veterinary Medical Association 200, 1648-1650
Bostock, D. E. (1973) The prognosis following surgical removal of mastocytomas
in dogs. Journal of Small Animal Practice 14, 27-41
Bostock, D. E. & Owen, L. N. (1972) Chemotherapy of canine and feline neoplasia.
Journal of Small Animal Practice 13, 359-367
Bray, J. P. (2016a) Soft tissue sarcoma in the dog – part 1: a current review. Journal
of Small Animal Practice 57, 510-519
Bray, J. P. (2016b) Soft tissue sarcoma in the dog – part 2: surgical margins, con-
troversies and a comparative review. Journal of Small Animal Practice 58, 63-72
Bray, J. P., Polton, G. A., McSporran, K. D., et al. (2014) Canine soft tissue sarcoma
managed in first opinion practice: outcome in 350 cases. Veterinary Surgery
43, 774-782
Bronden, L. B., Nielsen, S. S., Toft, N., et al. (2010) Data from the Danish veteri-
nary cancer registry on the occurrence and distribution of neoplasms in dogs in
Denmark. Veterinary Record 166, 586-590
Bronson, R. T. (1982) Variation in age at death of dogs of different sexes and
breeds. American Journal of Veterinary Research 43, 2057-2059
Brown, P. M., Tzannes, S., Nguyen, S., et al. (2018) LOPP chemotherapy as first
line treatment for dogs with T cell lymphoma. Veterinary and Comparative Oncol-
ogy 16, 108-113
Carter, R.F., Harris, C.K., Withrow,S.J., Valli, V.E.O. & Susaneck, S.J. (1987) Che-
motherapy of canine lymphoma with histopathological correlation: doxorubicin
alone compared to COP as first treatment regimen. Journal of the American
Animal Hospital Association 23, 587-596
Chase, D., Bray, J. & Ide, A. (2009) Outcome following removal of canine spindle
cell tumours in first opinion practice: 104 cases. Journal of Small Animal Prac-
tice 50, 568-574
10 Journal of Small Animal Practice • © 2019 British Small Animal Veterinary Association
Comazzi, S. & Gelain, M. E. (2011) Use of flow cytometric immunophenotyping to
refine the cytological diagnosis of canine lymphoma. Veterinary Journal 188,
149-155
Comazzi, S., Marconato, L., Argyle, D. J., et al. (2015) The European Canine Lym-
phoma Network: a joining initiative to generate consensus guidelines for the
diagnosis and therapy in canine lymphoma and research partnership. Veteri-
nary and Comparative Oncology 13, 494-497
Cotchin, E. (1959) Some tumours of dogs and cats of comparative veterinary and
human interest. Veterinary Record 71, 1040-1050
Cotter, S. M. (1983) Treatment of lymphoma and leukaemia with cyclophospha-
mide, vincristine, and prednisolone: I treatment of dogs. Journal of the American
Animal Hospital Association 19, 159-165
Deravi, N., Berke, O., Woods, J. P. & Bienzie, D. (2017) Specific immuno types
of canine T cell lymphoma are associated with different outcomes. Veterinary
Immunology and immunopathology 191, 5-13
Demetriou, J. L., Brearely, M. J. & Constantino-Casas, F. (2012) Intentional mar-
ginal excision of canine limb sarcoma followed by radiotherapy. The Journal of
Small Animal Practice 53, 174-181
Dennis, M. M., McSporran, K. D., Bacon, N. J., et al. (2011) Prognostic factors for
cutaneous and subcutaneous soft tissue sarcomas in dogs. Veterinary Pathol-
ogy 48, 73-84
Dernell, W. S., Withrow, S. J., Kuntz, C. A., et al. (1998) Principles of treat-
ment for soft tissue sarcoma. Clinical Techniques in Small Animal Practice
13, 59-64
Dobson, J. M. & Gorman, N. T. (1994) Canine multicentric lymphoma II: response
to treatment by two different chemotherapeutic protocols. The Journal of Small
Animal Practice 35, 9-15
Dobson, J. M., Blackwood, L. B., McInnes, E. F., et al. (2001) Prognostic variables
in canine multicentric lymphosarcoma. The Journal of Small Animal Practice 42,
377-384
Dobson, J. M., Samuel, S., Milstein, H., et al. (2002) Canine neoplasia in the UK:
estimates of incidence rates from a population of insured dogs. The Journal of
Small Animal Practice 43, 240-246
Dobson, J., Cohen, S. & Gould, S. (2004) Treatment of canine mast cell tumours
with prednisolone and radiotherapy. Veterinary and Comparative Oncology 2,
132-141
Dorn, C. R., Taylor, D. O., Schneider, R., et al. (1968) Survey of animal neoplasms
in alameda and contra Costa counties, California II. Cancer morbidity in dogs
and cats from Alameda County. Journal of the National Cancer Institute 40,
307-318
Ehrhart, N. (2005) Soft tissue sarcomas in dogs: a review. Journal of the American
Animal Hospital Association 41, 241-246
Fernebro, J., Wiklund, M., Jonsson, J., et al. (2006) Focus on the tumour periphery
in MRI evaluation of soft tissue sarcoma: infiltrative growth signifies poor prog-
nosis. Sarcoma 21251, 1-5
Fournel-Fleury, C., Magnol, J. P., Bricaire, P., et al. (1997) Cytohistological and
immunological classification of canine malignant lymphomas: comparison
with human non-Hodgkin’s lymphomas. Journal of Comparative Pathology 117,
35-59
Frantz, A. M., Sarver, A. L., Ito, D., et al. (2013) Molecular profiling revelals prog-
nostically significant subtypes of canine lymphoma. Veterinary Pathology 50,
693-703
Friedrichs, K. R., Thomas, C., Plier, M., et al. (2010) Evaluation of serum ferritin
as a tumor marker for canine histiocytic sarcoma. Journal of Veterinary Internal
Medicine 24, 904-911
Gil da Costa, R. M. (2015) C-kit as a prognostic and therapeutic marker in canine
cutaneous mast cell tumours. From laboratory to clinic Vet J 205, 5-10
Goldschmidt, M. H. & Shofer, F. S. (1992) Skin Tumours of the Cat and Dog. Pub
Pergamon Press, Oxford, NY, USA
Greenlee, P. G., Filippa, D. A., Quimby, F. W., et al. (1990) Lymphoma in dogs. A
morphologic, immunologic and clinical study. Cancer 66, 480-490
Hahn, K. A., Ogilvie, G. & Rusk, T. (2008) Masitinib is a safe and effective treat-
ment for canine mast cell tumours. Journal of Veterinary Internal Medicine 22,
1301-1309
Hayes, A., Adams, V., Smith, K., et al. (2007) Vinblastine and prednisolone chemo-
therapy for surgically excised grade III canine cutaneous mast cell tumours. Vet
comp Oncol. Sep 5, 168-176
Hendrick, M. J., Goldschmidt, M. H., Shofer, F. S., et al. (1992) Postvaccinal sarco-
mas in the cat, epidemiology and electron probe microanalytical identification
of aluminium. Cancer Research 52, 5391-5394
Hohenhaus, A. E., Kelsey, J. L., Haddad, J., et al. (2016) Canine cutaneous and
subcutaneous soft tissue sarcoma: an evidence based review of case manage-
ment. Journal of the American Animal Hospital Association 52, 77-89
Hume, D. Z., Solomon, J. A. & Weisse, C. (2006) Palliative stenting for malignant
colonic obstruction in two cats. Journal of the American Veterinary Medical Asso-
ciation 228, 392-396
Jourdier, T.-M., Moste, C., Bonnet, M.-C., et al. (2003) Local immunotherapy of
spontaneous feline fibrosarcoma using recombinant poxviruses expressing
interleukin 2 (IL). Gene Therapy 10, 2126-2132
Kamstock, D. A., Ehrhart, E. J., Getzy, D., et al. (2011) Recommended guide-
lines  for submission, trimming margin evaluation and reporting of tumor
biopsy  specimens in veterinary surgical pathology. Veterinary Pathology 48,
19-31
 Veterinary oncology 60 years
Keller, E. T., MacEwen, E. G., Rosenthal, R. C., et al. (1993) Evaluation of prog-
nostic factors and sequential combination chemotherapy with doxorubicin for
canine lymphoma. Journal of Veterinary Internal Medicine 7, 289-295
Keller, S. M., Vernau, W. & Moore, P. F. (2016) Clonality testing in veterinary medi-
cine: a review with diagnostic guidelines. Veterinary Pathology 53, 711-725
Kerlin, R. L. & Hendrick, M. J. (1996) Malignant fibrous histiocytoma and malig-
nant histiocytosis in the dog – convergent or divergent phenotypic differentia-
tion? Veterinary Pathology 33, 713-716
Killick, D. R., Stell, A. J. & Catchpole, B. (2015) Immunotherpay for cancer – is
it time to go back to the future? Journal of Small Animal Practice 56, 229-241
Kiupel, M., Webster, J. D., Bailey, K. L., et al. (2011) Proposal of a 2-tier histologi-
cal grading system for canine cutaneous mast cell tumors to more accurately
predict biological behavior. Veterinary Pathology 48, 147-155
Koher, G. & Milstein, C. (1975) Continuous cultures of fused cells secreting anti-
body of predefined specificity. Nature 256, 495-497
Kraun, M. B., Nelson, N. C. & Hollinger, C. (2015) Imaging diagnosis – computed
tomographic, surgical and histopathological characteristics of and infiltrative
aniolipoma in a dog. Veteerinary Radiology & Ultrasound 56, E31-E35
Krick, E. L., Billings, A. P., Shofer, F. S., et al. (2009) Cytological lymph node evalu-
ation in dogs with cutaneous mast cell tumors: association with grade and
survival. Veterinary and Comparative Oncology 7, 130-138
Kuntz, C. A., Dernell, W. S., Powers, B. E., et al. (1997) Prognostic factors for surgi-
cal treatment of soft-tissue sarcomas in dogs: 75 cases (1986-1996). Journal
of the American Veterinary Medical Association 211, 1147-1151
Ladlow, J. (2013) Injection site-associated sarecoma in the cat: treatment recom-
mendations and results to date. Journal of Feline Medicine and Surgery 15,
409-418
Lane, J., Price, J., Moore, A., et al. (2018) Low-grade gastrointestinal lymphoma in
dogs: 20 cases (2010 to 2016). Journal of Small Animal Practice 59, 147-153
London, C. (2004) Kinase inhibitors in cancer therapy. Veterinary and Comparative
Oncology 2, 177-193
London, C. A., Malpas, P. B. & Wood-Follis, S. L. (2009) Multi-center, placebo-con-
trolled, double-blind, randomized study of oral toceranib phosphate (SU11654),
a receptor tyrosine kinase inhibitor, for the treatment of dogs with recurrent
(either local or distant) mast cell tumor following surgical excision. Clinical Can-
cer Research 15, 3856-3865
MacEwen, E. G., Brown, N. O., Patnaik, A. K., et al. (1981) Cyclic combination che-
motherapy of canine lymphosarcoma. Journal of the American Veterinary Medi-
cal Association 178, 1178-1181
Madewell, B. R. (1975) Chemotherapy for canine lymphosarcoma. American Jour-
nal of Veterinary Research 36, 1525-1528
Marcanato, L. (2011) The staging and treatment of multicentric high-grade lym-
phoma in dogs: a review of recent developments and future prospects. Veteri-
nary Journal 188, 34-38
Marconato, L., Polton, G. A., Sabattini, S., et al. (2017) European canine lymphoma
network. Conformity and controversies in the diagnosis,. Staging and follow-up
evaluation of canine nodal lymphoma: a systematic review of the last 15 years
of published literature. Veterinary and Comparative Oncology 15, 1029-1040
Mazzaccari, K., Boston, S. E., Toskich, B. B., et al. (2017) Video-assisted micro-
wave ablation for the treatment of a metastatic lung lesion in a dog with appen-
dicular osteosarcoma and hypertrophic osteopathy. Veterinary Surgery 46,
1161-1165
McCaw, D. L., Miller, M. A., Ogilvie, G. K., et al. (1994) Response of canine mast
cell tumors to treatment with oral prednisone. Journal of Veterinary Internal
Medicine 8, 406-408
McKnight, J. A., Maudlin, G. N., McEntee, M. C., et al. (2000) Radiation treatment
for incompletely resected soft-tissue sarcomas in dogs. Journal of the American
Veterinary Medical Association 217, 205-210
Merlo, D. F., Rossi, L., Pellegrino, C., et al. (2008) Cancer incidence in pet dogs;
findings of the animal tumor registry on Genoa, Italy. Journal of Veterinary Inter-
nal Medicine 22, 976-984
Miller, R. L., VanLelyvel, S., Warland, J., et al. (2016) A retrospective review of
treatment and response of high-grade mast cell tumours in dogs. Veterinary &
Comparative Oncology 14, 361-370
Mischke, R., Waterson, M. & Eckersall, P. D. (2007) Changes in C-reactive protein
and haptoglobin in dogs with lymphatic neoplasia. The Veterinary Journal 174,
188-192
Mochizuki, H., Shapiro, S. G. & Breen, M. (2015) Detection of BRAF mutation in
urine DNA as a molecular diagnostic for canine urothelial and prostatic carci-
noma. PLoS One 10, e0144170
Moore, P. F., Rossitto, P. V., Danilenko, D. M., et al. (1992) Monoclonal antibodies
specific for canine CD4 and CD8 define functional T-lymphocyte subsets and
high density expression of CD4 by canine neutrophils. Tissue Antigens 40, 75-
85
Morgan, E., O’Connell, K., Thomson, M., et al. (2018) Canine T cell lymphoma
treated with lomustine, vincristine procarbazine and prednisolone chemother-
apy in 35 dogs. Veterinary and Comparative Oncology 16, 622-629
Moulton, J. E. (1961) Tumors in Domestic Animals. 1st edn. University of Califor-
nia Press, Berkeley, Los Angeles
Nolan, M. W. & Dobson, J. M. (2018) The future of radiotherapy in small animals –
should the fractions be coarse or fine? Journal of Small Animal Practice 59, 521
Owen, L. N. (1960) Recent treatments of malignant neoplasia. Journal of Small
Animal Practice 1, 116-129
Journal of Small Animal Practice • © 2019 British Small Animal Veterinary Association 11
Park, S. B., Park, J. M., Moon, S. H., et al. (2018) Role of 18F-FDG PET/CT in
patients without known primary malignancy with skeletal lesions suspicious for
cancer metastasis. PloS One 13, e0196808
Patnaik, A. K., Ehler, W. J. & MacEwen, E. G. (1984) Canine cutaneous mast cell
tumour: morphologic grading and survival time in 83 dogs. Veterinary Pathology
21, 469-474
Pierezan, F., Mansell, J., Ambrus, A., et al. (2014) Immunohistochemical expres-
sion of ionized calcium binding adapter molecule 1 in cutaneous histiocytic
proliferative, neoplastic and inflammatory disorders of dogs and cats. Journal
of Comparative Pathology 151, 347-351
Planellas, M., Bassols, A., Siracusa, C., et al. (2009) Evaluation of serum hapto-
globin and C-reactive protein in dogs with mammary tumors. Veterinary Clinical
Pathology 38, 348-352
Pollard, R. E., Long, C. D., Nelson, R. W., et al. (2001) Percutaneous ultrasono-
graphically guided radiofrequency heat ablation for treatment of primary hyper-
parathyroidism in dogs. Journal of the American Veterinary Medical Association
218, 1106-1110
Ponce, F., Magnol, J. P., Ledieu, D., et al. (2004) Prognostic significance of mor-
phological subtypes in canine malignant lymphomas during chemotherapy. The
Veterinary Journal 167, 158-166
Ponce, F., Marchal, T., Magnol, J. P., et al. (2010) A morphologic study of 608 cases
of canine malignant lymphoma in France with a focus on comparative simi-
larities between canine and human lymphoma morphology. Veterinary Pathology
47, 414-433
Postorino, N. C., Susaneck, S. J., Withrow, S. J., et al. (1989) Single agent therapy
with adriamycin for canine lymphoma. Journal of the American Animal Hospital
Association 25, 221-225
Priester, W. A. & McKay, F. W. (1980) The occurrence of tumors in domestic ani-
mals. National Cancer Institute Monograph 54, 158
Prpich, C. Y., Santamaria, A. C., Simcock, J. O., et al. (2013) Second intention heal-
ing after wide excision of soft tissue sarcomas in the distal aspects of the limbs
in dogs: 31 cases (2005 – 2012). Journal of the American Veterinary Medical
Association 244, 187-194
Rassnick, K. M., Moore, A. S., Williams, L. E., et al. (1999) Treatment of canine
mast cell tumours with CCNU (Lomustine). Journal of Veterinary Internal Medi-
cine 13, 601-605
Reid-Smith RJ, Bonnett BN, Martin SW, et al (2000) The incidence of neoplasia in
the canine and feline patient populations of private veterinary practices in south-
ern Ontario. Proceedings of the 9th symposium of the International Society for
Veterinary Epidemiology and Economics. Colorado, August 2000, p 935-955.
Romatowski, J. (1997) Recommendations of the vaccine-associated feline sar-
coma task force. Journal of the American Veterinary Medical Association 210,
890
Sayag, D., Flournel-Fleury, C. & Ponce, F. (2018) Prognsotic significance of morpho-
types in canine lymphoma. A systematic review of literature vet com. Oncologia
16, 12-19
Scase, T. J., Edwards, D., Miller, J., et al. (2006) Canine mast cell tumors: correla-
tion of apoptosis and proliferation markers with prognosis. Journal of Veterinary
Internal Medicine 20, 151-158
Schlicksup, C., Weisse, A. & Berent, J. A. (2009) Solomon use of endovascular
stents in three dogs with Budd-Chiari syndrome. Journal of the American Veteri-
nary Medical Association 235, 544-550
Selting, K. A., Ringold, R., Husbands, B., et al. (2016) Thymidine kinase type 1 and
C-reactive protein concentrations in dogs with spontaneously occurring cancer.
Journal of Veterinary Internal Medicine 30, 1159-1166
Silver, I. A. (1972) Use of radiotherapy for the treatment of malignant neoplasms.
Journal of Small Animal Practice 13, 351-358
Skinner, O. T., Boston, S. E., Giglio, R. E., et al. (2018) Diagnostic accuracy of
contrast-enhanced computed tomography for assessment of mandibular and
medial retropharyngeal lymph node metastasis in dogs with oral and nasal
cancer. Veterinary and Comparative Oncology 16, 562-570
Smrkovski, O. A., Essick, L., Rohrbach, B. W., et al. (2013) Masitinib mesylate for
metastatic and non-resectable canine cutaneous mast cell tumours. Veterinary
and Comparative Oncology. 13, 314-321
Squire, R. A., Bush, M., Melby, E. C., et al. (1973) Clinical and pathological study
of canine lymphoma: clinical staging. cell classification and therapy. Journal of
the National Cancer Institute 51, 565-574
Teske, E., Wisman, P., Moore, P. F., et al. (1994) Histological classification and
immunotyping in canine malignant lymphomas. An unexpected high frequency
of T-cell lymphomas with B-cell morphology. Experimental Haematology 22,
1179-1187
Tilki, D., Kin, S., Dall’Era, M. A., et al. (2015) Ultrasensitive prostate specific anti-
gen and its role after radical prostatectomy: A systematic review. The Journal of
Urology 193, 1525-1531
Valli, V. E., Jacobs, R. M., Parodi, A. L., et al. (2002) WHO Histological Classification
of Haematopoietic Tumours of Domestic Animals, Pub by Armed Forces Institute
of Pathology, Vol. 3. American Registry of Pathology, Washington DC Second series
Van Lelyveld, S., Miller, R., Warland, J., et al. (2015) Comparison of Ki67 and
mitotic index for predicting outcome in canine mast cell tumours. Journal of
Small Animal Practice 56, 312-319
Vascellari, M., Baioni, E., Ru, G., et al. (2009) Animal tumour registry of two prov-
inces in northern Italy: incidence of spontaneous tumours in dogs and cats.
BMC Veterinary Research 5, 39
 J. M. Dobson

Von Euler, H. P., Rivera, P., Aronsson, A. C., et al. (2009) Monitoring therapy in
canine malignant lymphoma and leukaemia with seruym thymidine kinase 1
activity – evaluation of a new, fully automated non-radiometric assay. Interna-
tional Journal of Oncology 34, 505-510
Warland, J., Amores-Fuster, I., Newbury, W., et al. (2014) The utility of staging in
canine mast cell tumours. Veterinary & Comparative Oncology 12, 287-298
Webster, J. D., Kiupel, M. & Yuzbasiyan-Gurkan, V. (2006) Evaluation of the
kinase  domain of c-KIT in canine cutaneous mast cell tumors. BMC Cancer
6, 85
Weishaar, K. M., Thamm, D. H., Warley, D. R., et al. (2014) Correlation of nodal
mast cells with clinical outcome in dogs with mast cell tumour and a proposed
classification system for the evaluation of nodal metastases. Journal of Com-
parative Pathology 151, 329-338
Wisner, E. R., Dickinson, P. J. & Higgins, R. J. (2011) Magnetic resonance imaging features
of canine intracranial neoplasia. Veterinary Radiology and Ultrasound 52, S52-S61
Yang, T., Case, J. B., Boston, S., et al. (2017) Microwave ablation for treatment
of hepatic neoplasia in five dogs. Journal of the American Veterinary Medical
Association 250, 79-85

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