animals

Review
Feline Soft Tissue Sarcomas: A Review of the Classification and
Histological Grading, with Comparison to Human and Canine
Melanie Dobromylskyj

Histopathology Department, Finn Pathologists, One Eyed Lane, Weybread, Diss IP21 5TT, Norfolk, UK;
[email protected]

Simple Summary: Soft tissue sarcomas are a common form of cancer arising in the skin and con-
nective tissues of domestic cats. Soft tissue sarcomas encompass a group of different histological
subtypes of tumours, which can behave in a range of different ways in the patient. In dogs and in
humans, this group of tumours can be given a histological score (“grade”) at the time of diagnosis,
which is prognostic, but there is no equivalent, well-established grading system for these tumours
in cats. This review looks at soft tissue sarcomas in terms of which histological subtypes of tumour
should be included in this group, and how pathologists approach their grading, comparing feline
tumours with their human and canine counterparts.

Abstract: Soft tissue sarcomas are one of the most commonly diagnosed tumours arising in the skin
and subcutis of our domestic cats, and are malignant neoplasms with a range of histological presenta-
tions and potential biological behaviours. However, unlike their canine and human counterparts,
there is no well-established histological grading system for pathologists to apply to these tumours, in
order to provide a more accurate and refined prognosis. The situation is further complicated by the
presence of feline injection site sarcomas as an entity, as well as confusion over terminology for this
Citation: Dobromylskyj, M. Feline
Soft Tissue Sarcomas: A Review of
group of tumours and which histological types should be included. There is also an absence of large
the Classification and Histological scale studies. This review looks at these tumours in domestic cats, their classification and histological
Grading, with Comparison to grading, with comparisons to the human and canine grading system.
Human and Canine. Animals 2022, 12,
2736. https://doi.org/10.3390/ Keywords: feline; cat; sarcoma; fibrosarcoma; tumour; soft tissue; injection site; grading; prognosis
ani12202736

Academic Editors: Gustavo A.

Ramirez, Alejandro Suárez-Bonnet
and Jéssica Molín
1. Introduction
Soft tissue sarcomas (STS) are a group of commonly diagnosed tumours in domestic
Received: 14 September 2022
cats. These are malignant neoplasms, with a range of histological subtypes and also of
Accepted: 10 October 2022
potential biological behaviours [1–3]. In this review, the sometimes confusing terminology
Published: 12 October 2022
surrounding these tumours is discussed, together with the prevalence of these tumours
Publisher’s Note: MDPI stays neutral in cats and their clinical behaviour in dogs and cats. The aims of this review are also to
with regard to jurisdictional claims in explore the different histological subtypes included in the group “soft tissue sarcomas” in
published maps and institutional affil- cats, dogs and in humans, the grading scheme applied to canine and human STSs and the
iations. grading system which has been proposed for feline STS. The review also looks at feline
injection site sarcomas, the role of immunohistochemical markers, and the subjectivity of
histological grading.
Copyright: © 2022 by the author. 2. Terminology
Licensee MDPI, Basel, Switzerland.
This article is an open access article
The terminology surrounding these tumours can be confusing, partly because there
distributed under the terms and
are a myriad of terms used in the published literature for these neoplasms. Mesenchymal
conditions of the Creative Commons
neoplasms are those which arise from mesenchymal cell types, and these can be either
Attribution (CC BY) license (https:// malignant or benign; the term sarcoma is typically used to denote malignant neoplasms of
creativecommons.org/licenses/by/ mesenchymal origin. Not all mesenchymal tumours arise from soft tissues though; they
4.0/). may, for example, arise from other tissues such as cartilage or bone. To slightly confuse

Animals 2022, 12, 2736. https://doi.org/10.3390/ani12202736 https://www.mdpi.com/journal/animals

Animals 2022, 12, 2736 2 of 12

the issue, mesenchymal tumours arising from soft tissues may demonstrate cartilage
and/or bone formation (for example, extra-skeletal chondrosarcoma, or extra-skeletal
osteosarcoma [4]. Whilst soft tissue sarcomas may potentially arise at any anatomical
location where soft mesenchymal tissue is present, those arising from the cutis and subcutis
are the focus of this review.
For a subset of these tumours derived from soft tissues, the traditional name used is
soft tissue sarcoma (STS) [5]. However, it has been suggested that “soft tissue tumours” or
“tumours of soft tissues” might be more appropriate terms, given that the word “sarcoma”
implies malignancy, but that it can sometimes be very difficult to differentiate low grade
malignant mesenchymal neoplasms from their benign counterparts [3,6]. Furthermore, for
the low grade malignant tumours in particular, these tend not to be life-threatening and to
not metastasize [1,2,5,7]. There has not been universal acceptance of this suggested change
in terminology to date however, and the name “soft tissue sarcoma” appears to be the most
commonly used and widely understood still.
The most recent publication [6] from the Davis Thompson DVM foundation (a group
created to further the education in veterinary and comparative pathology [8]) uses the
terminology “soft tissue tumours”; soft tissues for the purposes of that publication are
defined as “extra-skeletal connective tissues of the dermis, subcutis and fascia, striated
and smooth muscle, vessels, serosal and synovial linings and nerve sheaths.” Within this
broad tumour group, some histological types are considered together as a subgroup for
the purposes of grading and prognostication, despite having different mesenchymal cell
origins; these tumours are generally considered together due to their similar histological
features and biological behaviours in the patient. Diagnosis is typically made by his-
tological assessment and differentiating between the various histological subtypes with
confidence is not necessarily always possible by light microscopy alone [2,9–11]. A panel
of immunohistological stains are oftentimes needed to diagnose a more specific subtype
but is generally not warranted in a routine diagnostic setting given the similar biological
behaviours seen and the cost implications [1,9–13].

3. Prevalence of Soft Tissue Sarcomas in Cats

A retrospective study on the longevity and mortality of cats attending primary care
veterinary practices in England found that neoplasia was the fourth most common cause
of death in cats [14]. Of these, tumours arising in the skin and subcutis are the most
common form of neoplasia diagnosed in cats [15,16] and of those, more than half are
malignant [17,18].
It has long been known that STSs, encompassing fibrosarcomas and nerve sheath
tumours (NST) amongst other histological subtypes, are one of the most commonly diag-
nosed categories of neoplasia arising in the skin and subcutis of cats. Large scale studies in
the United Kingdom [17], Europe [16,18,19] and the USA [15] have all demonstrated, across
the decades and various continents, that fibrosarcomas/STSs consistently rank in the top
four when it comes to the most common tumours diagnosed in feline skin and soft tissues.
The typical age of a cat at the time of presentation for STS is 10–11 years [15,17,19], or
“middle aged or older” [16]. However, even in cats under the age of 12 months, malignant
mesenchymal neoplasms (i.e., those arising from any mesenchymal cell type, not only soft
tissue) have been reported to account for 16% of all tumours in this age group. Those
tumours arising from soft tissues specifically accounted for 15% overall, and the skin and
soft tissues was the most site at 41% [20].
Whilst discussing STS arising in young cats, it is worth mentioning feline sarcoma
virus (FeSV), a virus which arises from the combination of feline leukaemia virus (FeLV)
pro-viral particles with parts of the infected cat’s own genome. FeSV oncogenes promote
the transformation of fibroblasts and result in fibrosarcoma development. These account for
only a low percentage of fibrosarcomas in cats, but the tumours do tend to be multicentric,
carry increased risk of metastasis and occur in young cats predominantly [21,22].
Animals 2022, 12, 2736 3 of 12

Ho et al. [17] noted that several breeds, including Persian, Siamese, Burmese and
British Blue, had significantly lower odds of developing fibrosarcoma when compared with
a non-pedigree cat population.

4. Clinical Behaviour of Soft Tissue Sarcomas in Cats and Dogs

STSs as a whole, regardless of species, tend to be locally infiltrative and may often
extend along fascial planes; typically they are described as having a ‘pseudocapsule’ and a
relatively slow growth rate. In dogs, they tend to have a low to moderate incidence of metas-
tasis [1,2,5,7]. However, their clinical behaviour can vary and post-surgical recurrence was
shown to be a relatively common occurrence, for example in cats with fibrosarcomas [23],
thought to be due to often having poorly defined margins. STSs can be superficial and
mobile, or may infiltrate deeper tissues; they may persist for weeks to months with only
minor changes before undergoing rapid growth [24–26].
The existence of feline injection site sarcomas (FISS) further complicates the picture
for cats; these are tumours that arise at previous sites of vaccination (historically known as
vaccine-associated fibrosarcoma) or other forms of localised trauma which induce chronic
inflammation; a full review of FISS is outside of the scope of this current review, but there
are several reviews published [27–29] and the European Advisory Board on Cat Diseases
provides comprehensive and regularly updated information [30] on FISS.

5. Which Histological Subtypes Should Be Included in the STS Group?

(a) human:
In humans, STSs are considered to be relatively rare, accounting for approximately
1% of all malignant tumours in the adult population [31]. There are over 100 different
histological subtypes and the group includes tumours arising most commonly on the
trunk, extremities and also in the retroperitoneal space. The most commonly diagnosed
include liposarcoma, leiomyosarcoma and undifferentiated pleomorphic sarcoma (UPS); as
per the 2020 World Health Organisation classification of soft tissue tumours for humans,
these tumours are categorised as adipocytic, fibroblastic or myofibroblastic, fibrohistiocytic,
smooth muscle, pericytic, skeletal muscle, vascular, gastrointestinal, nerve sheath origin,
chondro-osseous, undifferentiated/unclassified or uncertain [31]. The general preference
is still to grade these tumours according to the system originally proposed by Trojani in
1984 [32], which will be discussed later, although there appears to be a growing recognition
that not all of these categories or histological subtypes behave in exactly the same way, and
that the same therapeutic approach is not necessarily optimal for all patients.
(b) canine:
In dogs, the group of STSs to which the grading scheme is typically applied includes
various histological subtypes including fibrosarcoma (including the keloidal variant), myx-
osarcoma, liposarcoma, perivascular wall tumours, nerve sheath tumours (NST, non-
plexus; also termed schwannomas, neurofibromas), pleomorphic sarcoma, undifferentiated
sarcoma and malignant mesenchymoma [3]. There are others which are generally excluded
from this group in terms of histological grading, including histiocytic sarcoma, lymphan-
giosarcoma, haemangiosarcoma, leiomyosarcoma, rhabdomyosarcoma and nerve sheath
tumours arising from plexi, together with oral fibrosarcoma, gastrointestinal stromal tu-
mours and synovial sarcoma. These are conventionally excluded from the group of STSs to
which the grading system is applied because either they can be consistently distinguished
by microscopic features and/or their anatomical location, and/or because they tend to
exhibit more malignant biological behaviour when compared to those subtypes which are
included [2,3,5–7]. More recently synovial sarcomas have been re-classified as peri-articular
myxosarcoma or peri-articular histiocytic sarcoma [6]. This approach in canines is different
to the one taken in humans; for dogs with STSs, this grouping becomes more a diagnosis
of exclusion.
Animals 2022, 12, 2736 4 of 12

In terms of relative prevalence, NSTs might be the most commonly occurring sub-
type [5], but over time the terminology used has been inconsistent and subject to change.
For example, haemangiopericytoma was previously a frequently used diagnostic term but
such tumours are now generally considered to be either perineural in origin or perivascular
wall tumours [12]. Haemangiopericytomas most likely represent a small subset of the
perivascular wall tumours, but without immunohistochemical staining these are difficult
to differentiate from nerve sheath tumours [33].
Thus, it can be seen that the histological subtypes included in the STS group for
human and canine patients varies, although there is overlap; there is also a difference in
the prevalence of the different subtypes between humans and dogs. Thus the subgroup of
STSs to which the grading is applied is not synonymous between the two species.
(c) feline:
For cats, there is less data about specific histological subtypes and their relative fre-
quencies, but the STS group would be likely to include NST, fibrosarcoma, myxosarcoma,
leiomyosarcoma, liposarcoma, rhabdomyosarcoma, perivascular wall tumours and un-
specified spindle cell tumours/sarcoma arising in the dermis or subcutis, regardless of
their degree of differentiation [6]. This poses a few questions; cats presumably can develop
perivascular wall tumours, but there is a lack of published data about them as a specific
subtype. Tumours previously referred to as “giant cell tumours of soft tissues” have now
been renamed as UPS, and appear to be included within the STS group [6]. FISS are
incorporated in the feline STS group for the purposes of discussing histological grading.

6. Histological Grading of STS

(a) Human:
The grading system for STS used in humans originated from a study which looked
at 155 patients with STSs of the various histological subtypes previously outlined [32]. In
this study, seven different and individual criteria or parameters were analysed (tumour
differentiation, tumour cellularity, atypical nuclei, malignant giant cells, mitotic count,
tumour necrosis and vascular emboli) and assessed against outcomes (survival time, time
to first metastasis and time to local recurrence). None of the seven criteria were significantly
associated with time to local recurrence, and those significantly associated with the survival
time and time to first metastasis were tumour differentiation, tumour cellularity, mitotic
count, tumour necrosis and vascular emboli. Of these, the authors then individually scored
tumour differentiation (scored 1 if well-differentiated, 2 if of uncertain histological type or
3 if embryonal, undifferentiated or of doubtful tumour type), mitotic count and tumour
necrosis, with the total score correlating to a grade of either low (grade I), intermediate
(grade II) or high (grade III), as shown in Table 1. However, it is important to note that the
criterion which had the best prognostic value, specifically degree of tumour differentiation,
is subjective in nature. Indeed the authors stated that “although the score system applied
was made as simple as possible, the subjectivity of evaluation may introduce problems in
the reproducibility of this grading” [32].
(b) canine:
This same grading system has been applied to dogs with STS in multiple studies [3,5,7].
One study found that canine STSs of higher histological grades were associated with a
higher chance of local recurrence and within a reduced timeframe, however, the histological
grade did not predict survival time [7]. Indeed, a comprehensive review of canine STS
grading studies found that overall there does not appear to be a clear consensus on the
association between histological grade and patient survival [3].
Animals 2022, 12, 2736 5 of 12

Table 1. Human soft tissue sarcoma grading system [32] as also routinely replied to canine soft
tissue sarcomas.

Differentiation Score
1 Sarcomas mostly resembling normal adult mesenchymal tissue
2 Sarcomas with known histological type but poor differentiation
3 Undifferentiated sarcomas, sarcomas of unknown type
Mitotic Score 1
1 0–9
2 10–19
3 More than 19
Tumour Necrosis Score
0 No necrosis
1 Equal to or less than 50% necrosis
2 More than 50% necrosis
Histological Grade 2
I Equal to or less than 3
II 4–5
III Equal to or more than 6
1Mitotic figures seen in 10 high power fields (400×). 2 total score when combining scores for differentiation,
mitotic count and tumour necrosis.

There are a number of suggested explanations for this. Firstly, many canines develop-
ing these tumours are older and may well die from other causes before metastatic disease
or local recurrence becomes fatal [3]. Secondly, these tumours are relatively slow growing
and often they can be managed locally without detrimental effects on quality of life. Even
when metastatic lesions occur, they are also likely to be slow growing and thus may not
impact on survival.
This is quite different to humans where it was shown that 62.6% of STS patients
developed metastatic disease, which accounted for 95.5% of the deaths; indeed, metastasis-
free curves and survival time curves plotted according to tumour grade were strikingly
similar to one another, highlighting the strong link between metastasis and survival time
in human patients [32]. For dogs (and cats), local recurrence would appear to be a more
frequent occurrence and the more likely cause of death when compared to humans with
STS. Or at least, it is presumed to be; even when metastatic disease or local recurrence is
suspected, it is very uncommon for it to be confirmed by biopsy and histopathological
assessment in dogs (or cats). Of course, decisions made around “end of life” are rather
different for veterinary patients.
It is also important to note that the likelihood of local recurrence is dependent on upon
the completeness of the surgical excision, but assessing the impact of this and disentangling
it from any effect of the histological grade on outcome is fraught with difficulties; this is
partly due to a lack of consistency when it comes to assessing surgical margins, and the
terminology used, such as “close”, “narrow”, “clear”. As such, it may be that the impact
of histological grade is most notable for patients with narrow or marginal excision of the
tumour but further studies are needed [2,3,9,34–36].
(c) feline injection site sarcoma:
There have been several published studies which have applied the human/canine STS
grading system in feline patients specifically diagnosed with FISS. One of these studies [37]
examined three categories of tumours, including primary FISS (n = 44), FISS with local
recurrence (n = 16) and non-vaccine associated fibrosarcomas (n = 10), however outcome
data was only available for the locally recurrent FISS group and therefore the prognostic
significance of the grade was not apparent [37]. Nevertheless, although there was a range of
histological grades for each group of tumours, it is interesting to note there was a tendency
for FISS to be of higher grade and the recurring FISS tumours had not assumed a more
Animals 2022, 12, 2736 6 of 12

anaplastic phenotype relative to the primary FISS tumour group [37]. Another study
in 2009 [38] was a retrospective analysis of radiation therapy as a treatment, in which a
proportion of the tumours were graded (n = 55/73) and neither the histological grade
nor the individual components were found to be predictive of survival or progression
free interval, (nor was the Ki67 score, which also did not correlate with the histological
grade) [38].
A more recent study by Porcellato et al. [39] divided 24 primary FISS cases into those
with local recurrence (n = 10) or none (n = 14), with a minimum follow-up interval of
24 months. In this study the authors assessed a wide range of factors, including the
histological grade, size of tumour, depth of infiltration, surgical margins, Ki67 score, and
mitotic count. Two factors were found to be prognostic in terms of local recurrence,
specifically the size of the tumour (after fixation, cut-off value of 3.75 cm) and the mitotic
count (20 per 10 high power fields), which was also prognostic in relation to mortality,
however the histological grade was not prognostic [39]. Thus on balance, there does not
seem to be any evidence to support the usefulness of applying the human/canine grading
system to FISS.
Some studies have focused on the immunohistochemical staining properties of FISS;
one such study [40] included 21 cases, 18 classified as fibrosarcomas, and three as sarcomas.
All tumours demonstrated positive staining for vimentin, 20 were positive staining for
S100, and four for desmin. Thirteen of the 21 tumours demonstrated a degree of positive
staining for Cox-2 and four for c-KIT.

7. Other Feline Soft Tissue Sarcomas

Other than the studies described above which looked specifically at FISS, and the
recent publication proposing a novel grading system for feline STSs [41], one other study
looking at the prognostication of subtypes of feline STS is Schulman et al. [42]. In this
study of 59 NSTs from 53 cats, there were three histologic categories. Sixteen tumours were
categorised as histologically malignant; those 16 tumours had four or more mitotic figures
in 10 high-power fields, and all bar one also had other histological features suggestive of
malignancy, including hypercellularity, significant nuclear atypia, and tumour necrosis.
The remaining tumours were classified as benign tumours with Antoni A areas that were
S-100 and glial fibrillary acid protein (GFAP) positive (n = 34), or benign tumours that
lacked Antoni A areas and were S-100 positive and GFAP negative (n = 9).
Alongside Schulman et al. [42], a few studies have looked at the immunohistochemical
staining properties of this group of tumours in cats; such studies tend to focus on a
particular histological subtype and/or single marker, trying to elucidate further the precise
cell of origin for these tumours. One further study examined feline cutaneous NST in
particular [43], with a total of 26 tumours of which 12 were classified as benign and
14 as malignant using similar criteria to Schulman et al. [42]. They reported all tumours
as having diffuse expression of vimentin, whilst 25 (96.2%) expressed neuron-specific
enolase (NSE), 24 (92.3%) expressed laminin and 25 (96.2%) expressed GFAP. Expression
of S100 was more variable; overall 17 cases (65.4%) demonstrated some positive staining
for S100, including both benign and malignant tumours (81.8% and 57.1% respectively),
and with variable intensity. Five tumours also expressed smooth muscle actin (SMA), four
of which were malignant. A case report published in 2018 [44] described a malignant
cutaneous NST with rhabdomyosarcomatous differentiation (termed a triton tumour) in
a cat. Immunohistochemical stains revealed diffuse strong expression of vimentin by
both cell populations and multifocal cytoplasmic and nuclear staining for S100. For some
markers, staining varied between areas, depending on cell differentiation; cells within some
areas expressed desmin and less apparent S100 staining and no staining for GFAP or SMA.
Desmin positive cells also expressed alpha sarcomeric actin and weak positive staining
for myoglobin.
A previous study [45] had also demonstrated immunoreactivity for KIT in 12 out of
46 cases (26%) of feline soft tissue fibrosarcomas, with four of those cases demonstrating
Animals 2022, 12, 2736 7 of 12

positive staining in greater than 80% of tumour cells. This KIT staining was described
as cytoplasmic and stippled within neoplastic spindle-shaped cells and/or multinucleate
giant cells, but did not appear to correlate with the tumour being a FISS.
Another recent study [46] examined feline giant cell pleomorphic sarcomas specifically
(also known as undifferentiated pleomorphic sarcoma, previously known as malignant
fibrous histiocytoma, anaplastic sarcoma with giant cells) with regards various features
including their immunohistochemical staining properties. Neoplastic cells of both types,
spindle cells and multinucleate giant cells, demonstrated positive staining for vimentin, as
well as for ionized calcium-binding adaptor molecule 1 (Iba-1); spindle cells demonstrated
strong positive cytoplasmic staining while the multinucleate giant cells demonstrated
membranous and/or cytoplasmic staining. Staining patterns were variable for desmin and
SMA, and staining for S100 was negative.

8. Impact of Histological Grading on Prognostication of Feline STS

Given how common STSs are in cats, and that they are malignant with a range of
potential biological behaviours, a grading system would be a valuable prognostic tool. To
this end, a recent study aimed to produce a grading system specific for feline tumours.
This retrospective study utilised a cohort of cats diagnosed with STS with a known clinical
outcome [41]. Histological assessment was performed blinded to outcome and a set of
potential criteria were each assessed individually, to identify those significantly associated
with outcome in their own right. The features assessed for each tumour included mitotic
count, presence of ulceration, necrosis (presence and extent), the size of the tumour, pres-
ence of any adjuvant-like material and multinucleate giant cells. Several of these criteria
were then combined to produce a feline-specific grading system (Table 2 and Figures 1–3).

Table 2. Proposed grading system from feline cutaneous and subcutaneous soft tissue sarcomas [41].

Inflammation Score
1 None, minimal or very mild
2 Mild to moderate
3 Severe
Mitotic Score 1
1 0–9
2 10–19
3 More than 19
Tumour Necrosis Score 2
0 No necrosis
1 Equal to or less than 50% necrosis
2 More than 50% necrosis
Histological Gradem 3
I Equal to or less than 3
II 4–5
III Equal to or more than 6
1 Mitotic figures seen in 10 high power fields (400×). 2 Necrosis as a percentage of tumour area present in sections.
3 total score when combining scores for differentiation, mitotic count and tumour necrosis.
 this end, a recent study aimed to produce a grading system specific for feline tumours.
This retrospective study utilised a cohort of cats diagnosed with STS with a known clinical
outcome [41]. Histological assessment was performed blinded to outcome and a set of
potential criteria were each assessed individually, to identify those significantly associ-
ated with outcome in their own right. The features assessed for each tumour included
mitotic count, presence of ulceration, necrosis (presence and extent), the size of the tu-
Animals 2022, 12, 2736 mour, presence of any adjuvant-like material and multinucleate giant cells. Several of 8 of 12
these criteria were then combined to produce a feline-specific grading system (Table 2 and
Figures 1–3).

(a) (b)
Figure 1. An example of a feline cutaneous soft tissue sarcoma of low histological grade (Grade I):
Figure(a) Anpower
1. low example of a feline cutaneous soft tissue sarcoma of low histological grade (Grade
view of the tumour within haired skin, with focal ulceration (HE-stained; 1× magni-
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Animals 2022, 12, x FOR PEER REVIEW a total score of 2 (HE-stained; 400× magnification). 8 of 12
2
(score 1), a mitotic count of 4 in 10 HPFs (400×; 2.37 mm ; score 1) and no necrosis (score 0)—giving
Animals 2022, 12, x FOR PEER REVIEW 8 of 12
a total score of 2 (HE-stained; 400× magnification).

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(a) (b)
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stained;highlight mitotic figures) and more than 50% necrosis (score 2)—total score 8 (HE-stained;
400× magnification).
400 × magnification).
Table 2. Proposed grading system from feline cutaneous and subcutaneous soft tissue sarcomas
Table 2. Proposed grading system from feline cutaneous and subcutaneous soft tissue sarcomas
[41].
[41].
Inflammation Score
Inflammation
1 Score None, minimal or very mild
21 None,
Mild tominimal or very mild
moderate
 sent in sections. 3 total score when combining scores for differentiation, mitotic count and tumour
necrosis.

When applied to the tumours in the study, there were statistically significant differ-
Animals 2022, 12, 2736 ences in median survival time between cats with tumours of differing grades (Figure 9 of 4).
12
When applied to the 47 cases with clinical outcome data available, 16 cats had grade I
tumours. Of those 16, three were reported as having died as a result of tumour-related
disease (TLR); in two cases treatment was not attempted and one had local recurrence
When applied to the tumours in the study, there were statistically significant differ-
with a survival time of 802 days. The median survival time (MST) was 900.5 days for cats
ences in median survival time between cats with tumours of differing grades (Figure 4).
diagnosed with grade I tumours. Fifteen of the 47 cats had grade II tumours. Of those, 8
When applied to the 47 cases with clinical outcome data available, 16 cats had grade I
were reported as having died as a result of TLR; six had local recurrence, one had sus-
tumours. Of those 16, three were reported as having died as a result of tumour-related
pected metastatic disease (not confirmed) and one was reported as tumour-related but the
disease (TLR); in two cases treatment was not attempted and one had local recurrence
cause of death was not otherwise specified. The MST was 514 days for cats diagnosed with
with a survival time of 802 days. The median survival time (MST) was 900.5 days for
grade II tumours. Sixteen of the 47 cats had grade III tumours. Of those, 11 were reported
cats diagnosed with grade I tumours. Fifteen of the 47 cats had grade II tumours. Of
as having died as a result of TLR; four had local recurrence, in four cases treatment was
those, 8 were reported as having died as a result of TLR; six had local recurrence, one had
not attempted,
suspected three disease
metastatic had suspected metastatic
(not confirmed) disease
and (notreported
one was confirmed). The MST was but
as tumour-related 283
days for cats diagnosed with grade III tumours [41].
the cause of death was not otherwise specified. The MST was 514 days for cats diagnosed
with Importantly, although
grade II tumours. the inflammation
Sixteen of the 47 catsscore is still III
had grade subjective,
tumours.which is not11
Of those, ideal,
wereit
replaced another subjective component in the human/canine system (specifically,
reported as having died as a result of TLR; four had local recurrence, in four cases treatment degree
of differentiation)
was not attempted,and a statistically
three had suspectedsignificant association
metastatic was confirmed).
disease (not found between
ThetheMSTdegree
was
of inflammation and survival time [41].
283 days for cats diagnosed with grade III tumours [41].

Figure 4.
Figure 4. Kaplan–Meier
Kaplan–Meier survival
survival curve
curve for
for histological
histological grade
grade [41].
[41]. The
The black
black line represents
represents cats
cats with
with
grade II (low
grade (low grade)
grade) soft
soft tissue
tissue sarcomas,
sarcomas, thethe blue
blue line
line represents
represents cats
cats with
with grade
grade IIII (intermediate
(intermediate
grade) soft
grade) soft tissue
tissue sarcomas
sarcomas and and the
the red
red line
line represents
represents cats
cats with
with grade
grade III
III (high
(high grade)
grade) softsoft tissue
tissue
sarcomas. Tick lines represent censored cases (lost to follow-up or died of non tumour-related
sarcomas. Tick lines represent censored cases (lost to follow-up or died of non tumour-related causes).
causes).
Importantly, although the inflammation score is still subjective, which is not ideal, it
9. Conclusions—Where
replaced another subjective Next for FelineinSoft
component the Tissue Sarcomas?
human/canine system (specifically, degree
The grading scheme
of differentiation) described above
and a statistically [41] isassociation
significant only a proposed system
was found and asthe
between such there
degree
is now
of a need forand
inflammation a larger scale,
survival preferably
time [41]. prospective studies to validate it fully, ideally
via multicentre collaborations. There are drawbacks to the proposed grading scheme, in-
9. Conclusions—Where
cluding precisely which Next for Feline
histological Soft Tissue
subtypes shouldSarcomas?
be included within the STS group
The grading
and whether FISSscheme
shoulddescribed
be includedabove [41] is
or not. If only a proposed
we decide system be
FISS should and as such there
addressed as a
is now a need
separate entity,for
wea need
largertoscale,
reachpreferably
a consensus prospective
on just how studies to validate
we diagnose FISS itwith
fully, ideally
certainty.
via multicentre
Reaching collaborations.
a consensus There
on such vital are drawbacks
questions to the proposed
requires collaboration andgrading scheme,
standardisation,
including
via such movements as the Veterinary Cancer Guidelines and Protocols group [47].group
precisely which histological subtypes should be included within the STS
and whether FISS should be included or not. If we decide FISS should be addressed as a
separate entity, we need to reach a consensus on just how we diagnose FISS with certainty.
Reaching a consensus on such vital questions requires collaboration and standardisation,
via such movements as the Veterinary Cancer Guidelines and Protocols group [47].
Another issue is the subjective nature of the inflammation score—although the dif-
ferentiation score it replaces in the Trojani scheme [32] is also subjective, it would be
advantageous if all criteria within any grading system were objective, readily obtainable
from routinely-stained haematoxylin and eosin sections and easy to reproduce, thereby
reducing variability between pathologists and laboratories [48,49]. With the advent and
increasing adoption of image analysis within veterinary pathology [50] it may be that
artificial intelligence plays an important role in quantifying criteria such as inflammation,
Animals 2022, 12, 2736 10 of 12

as well as other features such as the extent of necrosis [51], and mitotic counts [52] with
increased accuracy.
Given the frequency of STSs in felines and the potential for malignant behaviour, more
research is critical to give us a better understanding of this group of tumours. Large-scale,
prospective studies are also needed to further validate the recently proposed grading
system [41] and confirm its prognostic capabilities. Finally, more detailed investigations
into the underlying genetics of this group of tumours are warranted, both to help better
understand the biology of the disease and to aid in identifying potential diagnostic and
prognostic markers as well as possible therapeutic targets.

Funding: This research received no external funding.

Acknowledgments: The author would like to acknowledge the continued support of colleagues
and collaborators at Finn Pathologists, The Wellcome Sanger Institute and at the Royal Veterinary
College, UK.
Conflicts of Interest: The author declares no conflict of interest.

References
1. Bostock, D.E.; Dye, M.T. Prognosis after surgical excision of canine fibrous connective tissue sarcomas. Vet. Pathol. 1980, 17,
581–588. [CrossRef]
2. Chase, D.; Bray, J.; Ide, A.; Polton, G. Outcome following removal of canine spindle cell tumours in first opinion practice: 104
cases. J. Small Anim. Pract. 2009, 50, 568–574. [CrossRef] [PubMed]
3. Dennis, M.M.; McSporran, K.D.; Bacon, N.J.; Schulman, F.Y.; Foster, R.A.; Powers, B.E. Prognostic factors for cutaneous and
subcutaneous soft tissue sarcomas in dogs. Vet. Pathol. 2011, 48, 73–84. [CrossRef]
4. Patnaik, A.K. Canine extraskeletal osteosarcoma and chondrosarcoma: A clinicopathologic study of 14 cases. Vet. Pathol. 1990, 27,
46–55. [CrossRef]
5. Kuntz, C.A.; Dernell, W.S.; Powers, B.E.; Devitt, C.; Straw, R.C.; Withrow, S.J. Prognostic factors for surgical treatment of soft-tissue
sarcomas in dogs: 75 cases (1986–1996). J. Am. Vet. Med. Assoc. 1997, 211, 1147–1151.
6. Roccabianca, P.; Schulman, F.Y.; Avallone, G.; Foster, R.A.; Scruggs, J.L.; Dittmer, K.; Kiupel, M. Surgical Pathology of Tumors
of Domestic Animals: Volume 3: Tumors of Soft Tissue, 3rd ed.; Kiupel, M., Ed.; Davis-Thompson DVM Foundation: Gurnee, IL,
USA, 2021.
7. McSporran, K.D. Histologic grade predicts recurrence for marginally excised canine subcutaneous soft tissue sarcomas. Vet.
Pathol. 2009, 46, 928–933. [CrossRef]
8. The Davis-Thompson Foundation. Available online: https://davisthompsonfoundation.org (accessed on 7 October 2022).
9. Williamson, M.M.; Middleton, D.J. Cutaneous soft tissue tumours in dogs: Classification, differentiation, and histogenesis. Vet.
Dermatol. 1998, 9, 43–48. [CrossRef]
10. Gaitero, L.; Anor, S.; Fondevila, D.; Pumarola, M. Canine cutaneous spindle cell tumours with features of peripheral nerve sheath
tumours: A histopathological and immunohistochemical study. J. Comp. Pathol. 2008, 139, 16–23. [CrossRef]
11. Perez, J.; Bautista, M.J.; Rollon, E.; de Lara, F.C.; Carrasco, L.; Martin de las Mulas, J. Immunohistochemical characterization of
hemangiopericytomas and other spindle cell tumors in the dog. Vet. Pathol. 1996, 33, 391–397. [CrossRef]
12. Chijiwa, K.; Uchida, K.; Tateyama, S. Immunohistochemical evaluation of canine peripheral nerve sheath tumors and other soft
tissue sarcomas. Vet. Pathol. 2004, 41, 307–318. [CrossRef]
13. Mazzei, M.; Millanta, F.; Citi, S.; Lorenzi, D.; Poli, A. Haemangiopericytoma: Histological spectrum, immunohistochemical
characterization and prognosis. Vet. Dermatol. 2002, 13, 15–21. [CrossRef]
14. O’ Neill, D.G.; Church, D.B.; McGreevy, P.D.; Thomson, P.C.; Brodbelt, D.C. Longevity and mortality of cats attending primary
care veterinary practices in England. J. Feline Med. Surg. 2015, 17, 125–133. [CrossRef]
15. Miller, M.A.; Nelson, S.L.; Turk, J.R.; Pace, L.W.; Brown, T.P.; Shaw, D.P.; Fischer, J.R.; Gosser, H.S. Cutaneous neoplasia in 340 cats.
Vet. Pathol. 1991, 28, 389–395. [CrossRef]
16. Graf, R.; Grüntzig, K.; Hässig, M.; Axhausen, K.W.; Fabrikant, S.; Welle, M.; Meier, D.; Guscetti, F.; Folkers, G.; Otto, V.; et al.
Swiss Feline Cancer Registry: A retrospective study of the occurrence of tumours in cats in Switzerland from 1965 to 2008. J.
Comp. Pathol. 2015, 153, 266–277. [CrossRef]
17. Ho, N.T.; Smith, K.C.; Dobromylskyj, M.J. Retrospective study of more than 9000 feline cutaneous tumours in the UK: 2006–2013.
J. Feline Med. Surg. 2018, 20, 128–134. [CrossRef] [PubMed]
18. Graf, R.; Grüntzig, K.; Boo, G.; Hässig, M.; Axhausen, K.W.; Fabrikant, S.; Welle, M.; Meier, D.; Guscetti, F.; Folkers, G.; et al. Swiss
Feline Cancer Registry 1965–2008, the influence of sex, breed and age on tumour types and tumour locations. J. Comp. Pathol.
2016, 154, 195–210. [CrossRef]
19. Manuali, E.; Forte, C.; Vichi, G.; Genovese, D.A.; Mancini, D.; De Leo, A.A.P.; Cavicchioli, L.; Pierucci, P.; Zappulli, V. Tumours in
European Shorthair cats: A retrospective study of 680 cases. J. Feline Med. Surg. 2020, 22, 1095–1102. [CrossRef]
Animals 2022, 12, 2736 11 of 12

20. Schmidt, J.M.; North, S.M.; Freeman, K.P.; Ramiro-Ibañez, F. Feline paediatric oncology: Retrospective assessment of 233 tumours
from cats up to one year (1993 to 2008). J. Small Anim. Pract. 2010, 51, 306–311. [CrossRef]
21. Hardy, W.D.; Zuckerman, E.E.; MacEwen, E.G.; Hayes, A.A.; Essex, M. A feline leukaemia virus- and sarcoma virus-induced
tumour-specific antigen. Nature 1977, 270, 249–251. [CrossRef]
22. Macy, D.W.; Reeds, K.B. Chapter Three—Veterinary Cancer Etiology, Section B: Viral Carcinogenesis. In Cancer Management in
Small Animal Practice; Henry, C.J., Higginbotham, M.L., Eds.; Elsevier: Amsterdam, The Netherlands, 2010; pp. 16–27.
23. Davidson, E.B.; Gregory, C.R.; Kass, P.H. Surgical excision of soft tissue fibrosarcomas in cats. Vet. Surg. 1997, 26, 265–269.
[CrossRef]
24. Mauldin, G.N. Soft tissue sarcomas. Vet. Clin. N. Am. Small Anim. Pract. 1997, 27, 139–148. [CrossRef]
25. Dobson, J.M.; Samuel, S.; Milstein, H.; Rogers, K.; Wood, J.L. Canine neoplasia in the UK: Estimates of incidence rates from a
population of insured dogs. J. Small Anim. Pract. 2002, 43, 240–246. [CrossRef]
26. Liptak, J.M.; Forrest, L.J. Soft Tissue Sarcomas. In Small Animal Clinical Oncology, 4th ed.; Withrow, S.J., Vail, D.M., Eds.; Sanders
Elsevier: St Louis, MO, USA, 2007; pp. 425–454.
27. Dean, R.S.; Pfeiffer, D.U.; Adams, V.J. The incidence of feline injection site sarcomas in the United Kingdom. BMC Vet. Res. 2013,
9, 17. [CrossRef]
28. Ladlow, J. Injection site-associated sarcoma in the cat: Treatment recommendations and results to date. J. Feline Med. Surg. 2013,
15, 409–418. [CrossRef]
29. Martano, M.; Morello, E.; Buracco, P. Feline injection-site sarcoma: Past, present and future perspectives. Vet. J. 2011, 188, 136–141.
[CrossRef]
30. Feline Injection Site Sarcoma. Available online: www.abcdcastvets.org/feline-injection-site-sarcoma-2/ (accessed on 4 September 2022).
31. Gamboa, A.C.; Gronchi, A.; Cardona, K. Soft-tissue sarcoma in adults: An update on the current state of histiotype-specific
management in an era of personalised medicine. CA Cancer J. Clin. 2020, 70, 200–229. [CrossRef]
32. Trojani, M.; Contesso, G.; Coindre, J.M.; Rouesse, J.; Bui, N.B.; de Mascarel, A.; Goussot, J.F.; David, M.; Bonichon, F.; Lagarde, C.
Soft-tissue sarcomas of adults; study of pathological prognostic variables and definition of a histopathological grading system.
Int. J. Cancer. 1984, 33, 37–42. [CrossRef]
33. Avallone, G.; Helmbold, P.; Caniatti, M.; Stefanello, D.; Nayak, R.C.; Roccabianca, P. The spectrum of canine cutaneous perivascular
wall tumors: Morphologic, phenotypic, and clinical characterization. Vet. Pathol. 2007, 44, 607–620. [CrossRef]
34. Chiti, L.E.; Ferrari, R.; Roccabianca, P.; Boracchi, P.; Godizzi, F.; Busca, G.A.; Stefanello, D. Surgical margins in canine cutaneous
soft tissue sarcomas: A dichotomous classification system does not accurately predict the risk of local recurrence. Animals 2021,
11, 2367. [CrossRef]
35. Stefanello, D.; Morello, W.; Roccabianca, P.; Iussich, S.; Nassuato, C.; Martano, M.; Squassino, C.; Avallone, G.; Romussi, S.;
Buracco, P. Marginal excision of low-grade spindle cell sarcoma of canine extremities: 35 dogs (1996–2006). Vet. Surg. 2008, 37,
461–465. [CrossRef]
36. Bacon, N.J.; Dernell, W.S.; Ehrhart, N.; Powers, B.E.; Withrow, S.J. Evaluation of primary re-excision after recent inadequate
resection of soft tissue sarcomas in dogs: 41 cases (1999–2004). J. Am. Vet. Med. Assoc. 2007, 230, 548–554. [CrossRef]
37. Couto, S.S.; Griffey, S.M.; Duarte, P.C.; Madewell, B.R. Feline vaccine-associated fibrosarcoma: Morphological distinctions. Vet.
Pathol. 2002, 39, 33–40. [CrossRef]
38. Eckstein, C.; Guscetti, F.; Roos, M.; Martín de las Mulas, J.; Kaser-Hotz, B.; Rohrer Bley, C. A retrospective analysis of radiation
therapy for the treatment of feline vaccine-associated sarcoma. Vet. Comp. Oncol. 2009, 7, 54–68. [CrossRef]
39. Porcellato, I.; Menchetti, L.; Brachelente, C.; Sforna, M.; Reginato, A.; Lepri, E.; Mechelli, L. Feline Injection-Site Sarcoma. Vet.
Pathol. 2017, 54, 204–211. [CrossRef]
40. Carneiro, C.S.; de Queiroz, G.F.; Pinto, A.C.; Dagli, M.L.; Matera, J.M. Feline injection site sarcoma: Immunohistochemical
characteristics. J. Feline Med. Surg. 2019, 21, 314–321. [CrossRef]
41. Dobromylskyj, M.J.; Richards, V.; Smith, K.C. Prognostic factors and proposed grading system for cutaneous and subcutaneous
soft tissue sarcomas in cats, based on a retrospective study. J. Feline Med. Surg. 2021, 23, 168–174. [CrossRef]
42. Schulman, F.Y.; Johnson, T.O.; Facemire, P.R.; Fanburg-Smith, J.C. Feline Peripheral Nerve Sheath Tumors: Histologic, Immuno-
histochemical, and Clinicopathologic Correlation (59 Tumors in 53 Cats). Vet. Pathol. 2009, 46, 1166–1180. [CrossRef]
43. Mandara, M.T.; Fabriani, E.; Pavone, S.; Pumarola, M. Feline cutaneous nerve sheath tumours; histological features and
immunohistochemical evaluations. Res. Vet. Sci. 2013, 95, 548–555. [CrossRef]
44. Stoll, A.L.; Suárez-Bonnet, A.; Summers, B.A.; Priestnall, S.L. Malignant cutaneous peripheral nerve sheath tumour with
rhabdomyosarcomatous differentiation (triton tumour) in a domestic cat. J. Comp. Path. 2018, 165, 1–5. [CrossRef]
45. Smith, A.J.; Njaa, B.L.; Lamm, C.G. Immunohistochemical expression of c-KIT protein in feline soft tissue fibrosarcomas. Vet.
Pathol. 2009, 46, 934–939. [CrossRef]
46. de Cecco, B.S.; Argenta, F.F.; Bianchi, R.M.; De Lorenzo, C.; Wronski, J.G.; Bandinelli, M.B.; da Costa, F.V.; Driemeier, D.; Pavarini,
S.P.; Sonne, L. Feline giant-cell pleomorphic sarcoma: Cytologic, histologic and immunohistochemical characterization. J. Feline
Med. Surg. 2021, 23, 738–744. [CrossRef]
47. Veterinary Cancer Guidelines and Protocols. Available online: https://vcgp.org (accessed on 4 September 2022).
48. Avallone, G.; Rasotto, R.; Chambers, J.K.; Miller, A.D.; Behling-Kelly, E.; Monti, P.; Berlato, D.; Valenti, P.; Roccabianca, P. Review
of histological grading systems in veterinary medicine. Vet. Pathol. 2021, 58, 809–828. [CrossRef]
Animals 2022, 12, 2736 12 of 12

49. Meuten, D.J.; Moore, F.M.; Donovan, T.A.; Bertram, C.A.; Klopfleisch, R.; Foster, R.A.; Smedley, R.C.; Dark, M.J.; Milovancev, M.;
Stromberg, P.; et al. International Guidelines for Veterinary Tumor Pathology: A Call to Action. Vet. Pathol. 2021, 58, 766–794.
[CrossRef] [PubMed]
50. La Perle, K.M.D. Machine Learning and Veterinary Pathology: Be Not Afraid! Vet. Pathol. 2019, 56, 506–507. [CrossRef]
51. Rai, T.; Morisi, A.; Bacci, B.; Bacon, N.J.; Dark, M.J.; Aboellail, T.; Thomas, S.A.; Bober, M.; La Ragione, R.; Wells, K. Deep learning
for necrosis detection using canine perivascular wall tumour whole slide images. Sci. Rep. 2022, 12, 10634. [CrossRef]
52. Bertram, C.A.; Aubreville, M.; Donovan, T.A.; Bartel, A.; Wilm, F.; Marzahl, C.; Assenmacher, C.A.; Becker, K.; Bennett, M.; Corner,
S.; et al. Computer-assisted mitotic count using a deep learning-based algorithm improves interobserver reproducibility and
accuracy. Vet. Pathol. 2022, 59, 211–226. [CrossRef] [PubMed]