EQUINE VETERINARY EDUCATION 1

Equine vet. Educ. (2018)  () -

doi: 10.1111/eve.12926

Clinical Commentary
Cutaneous squamous cell carcinoma (SCC): “What’s the problem?”
D. C. Knottenbelt†* and J. S. Croft‡
†
Weipers Equine Centre, University of Glasgow, Glasgow; and ‡Equine Medical Solutions Ltd, Lomond Court,
Stirling, UK
*Corresponding author email: [email protected]
Keywords: horse; equine; carcinoma; cutaneous; aetiopathogenesis; metastasis

Squamous cell carcinoma (SCC) is a tumour of squamous play a part in its pathogenesis (Figs 2 and 4), alternative
epithelial cells and therefore, in theory at least, can affect carcinogens have to be considered.
any tissue with a squamous epithelium; these are of course In the case described by Poore et al. in this edition (2018),
found in the skin but also line the upper respiratory tract, the a carcinoma developed in nonpigmented skin around the
lower urinary tract and parts of the alimentary tract including anus – it is impossible again to believe that sunshine played a
the mouth, oesophagus and squamous portion of the part in its development. Other potential factors suggested to
stomach. be involved include chronic irritation or infection, cutaneous
Much has been written about this relatively common burns, poor wound healing and parasitic diseases (e.g.
tumour type in horses with many single reports, as in the case habronemiasis, onchocerciasis). In ocular sites, chronic
described in this edition by Poore et al. (2018), and a modest conjunctivitis, chronic nasolacrimal duct obstruction, and
number of case series. The variety of organs involved and the congenital or acquired eyelid deformities are all possible risk
challenges of diagnosis and management as well as the factors (Rebhun 1998). Seven horses diagnosed with ocular
unpredictability of definitive prognosis continue to perplex SCC had a documented previous eye injury (Runnells and
and concern practitioners and specialists alike. A broad Benbrook 1942).
summary of the detailed nature of this tumour is well- Cases of SCC of a deeply invasive nature with a high
described and fully referenced from a pathological and propensity for local destruction and potential malignancy
clinical perspective by Knottenbelt et al. (2015). have been identified at burn wound sites (Schumacher et al.
Overall results from several tumour surveys both in post- 1986) (Fig 5) and burn sites are probably heavily predisposed
mortem studies and in referrals to pathology services as well to carcinoma development. The reasons for this are not clear
as those to specialist centres confirm that squamous cell but local immune processes and genetic instability of the
carcinoma remains one of the most common equine affected cells may be involved. Exposure of burn sites to
cancers. It is estimated to comprise 7–31% of total neoplasms. strong sunlight can also be contributory (Fig 5a,b).
Horses of any age can be affected by SCC, with reports in Squamous cell carcinoma has also been identified in
animals as young as one year. However, it is most often wound sites with some regularity. If this wound healing
reported in mature horses. complication is overlooked it can lead to disastrous
The transformation of normal cells to an overt carcinoma consequences (Fig 6). A carcinoma is reported to have
is usually a gradual process involving a series of cellular occurred in exuberant granulation tissue at the site of a
mutations that allow the tumour to pass through a series of previous injection site abscess over the gluteal region,
developmental stages; these can be easily misinterpreted approximately 2 years following the initial incident (Baird and
until late in the progression of the condition. Common Frelier 1990). An aggressive SCC was also reported to
carcinogens that have been identified in horses include develop in a chronic wound at the site of a neck laceration
sunlight and other radiations, chemical exposure and viruses. that had been treated topically with various chemicals; it is
It is well known that nonpigmented skin is far more likely to be thought that the latter may be important in carcinoma
affected by carcinoma and oftentimes the protection pathogenesis (Fessler et al. 1993). Since the number of cases
afforded from pigmented skin is very clear in horses (Fig 1). reported in the literature is very small, it is almost impossible to
This is not always the case, however, and pigmented skin can identify specific carcinogens. It is important to remember that
be affected (Fig 2). any wound that fails to heal should be investigated and
The paper in this edition of Equine Veterinary Education there is therefore always clinical justification in submitting
(Poore et al. 2018) describes an unusual carcinoma location excised “granulation tissue” from even the earliest stages of
in an older horse. Although perianal carcinoma is very rare wound management. Early detection gives realistic changes
there are still some features that make the clinical diagnosis of treatment but any tumour developing at the site of a
easier. The fact that the skin described in this case was wound is extremely difficult to manage.
nonpigmented and the area ulcerated and destructive is Possibly the commonest site for carcinoma development
typical (Fig 3) although cannot be said to be in horses is the penile skin and to a slightly lesser degree the
pathognomonic; pigmented skin can be affected and some external and internal laminae of the prepuce. Here, again
carcinomas are proliferative (Fig 4). pigment plays a prominent but not exclusive role in
Notwithstanding the relationship between SCC and susceptibility to SCC (Fig 4). It has been suggested that viral
sunlight (UV) exposure of nonpigmented skin and/or squamous infection with Equus caballus papilloma virus-2 (EcPV2) or
cell mucous membranes (such as the conjunctiva), SCC does bovine papilloma virus might be in some way responsible
occur on pigmented skin and in areas where the sun “doesn’t since both can often be found associated with SCC in this
shine”! In these areas where sunlight exposure is unlikely to site. For SCC of the male genitalia smegma is also suggested

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2 Cutaneous squamous cell carcinoma

Fig 1: A 9-year-old coloured gelding developed an aggressive

SCC of the nonpigmented portion of the lower eyelid. The
pigmented portion was spared and histologically the tumour Fig 3: An ulcerated and destructive carcinoma occurring on a
did not invade the pigmented skin. The ‘cut-off’ is very obvious nonpigmented portion of the upper lip. (Picture courtesy of Nicky
in spite of the highly destructive and proliferative, poorly Pursey.)
differentiated SCC tumour.

Fig 4: This 14-year-old pony gelding was diagnosed by biopsy

with an aggressive invasive but proliferative carcinoma. Note the
seeded carcinoma sites in the adjacent skin (arrow) and the lack
of pigment. (Picture courtesy of Sam Harding).

or even an exacerbating irritant (Brinsko 1998). The penile

forms of SCC are a particularly interesting subset of the
cancer. A comprehensive and excellent study on the
pathogenesis and treatment of penile SCC by Van den Top
et al. (2010) confirms that the condition usually starts out
with a squamous dysplasia and epidermal hypertrophy.
This gradually loses differentiation and ultimately loses its
Fig 2: An extensive SCC in the strongly pigmented perineal proliferative nature (squamous papilloma) in favour of a more
region of a 14-year-old maiden mare. In this case, it is impossible destructive carcinoma. This latter stage results in significant
to believe that sunlight played any role in the aetiopathogenesis welfare compromise and brings surgical and medical
of this aggressive and rapidly progressive tumour complex. It is challenges.
also hard to imagine what carcinogen might be involved here
The pathogenesis of carcinoma follows an almost classic
although the shape and extent of the lesion might suggest some
course in all species and the horse is no exception. The
chronic irritation arising from rectal fluids.
diagram shown here illustrates the development of
carcinoma from an early dysplastic information of mildly
to be a significant aspect of the aetiopathogenesis mainly on abnormal cells to a highly malignant and metastatic form.
the basis of the much higher prevalence in older geldings. It Fortunately, metastasis is not common in the horse. It is,
could be considered to be a primary carcinogen of course however, an important aspect of the management of

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D. C. Knottenbelt and J. S. Croft 3

mutations are critical in the development of a large

a)
proportion of human cases of SCC (Brash et al. 1991). Similar
P53 impairment has been found in a proportion of SCC cases
in horses and in particular those affecting the genitalia (Pazzi
et al. 1996). In the majority of carcinoma tumours in most
species there is a significant impairment to the P53 function
and this imparts both a lack of control on the cell cycle and
an inherent genetic instability. The cell becomes increasingly
liable to genetic insult and further mutation with relatively less
insult. Sequential mutations lead the tumour clone towards
malignancy.
From a clinical perspective the mutational changes can be
correlated with the genetic changes (Fig 7). The earliest stages
are usually manifest as a squamous papilloma or a squamous
cell dysplasia (Fig 7). These stages are easily overlooked or
misdiagnosed. The sequential mutations within the transformed
cell gradually shifts the cell behaviour from a dysplastic,
proliferative intraepithelial (in situ carcinoma) state to a state
b) where the tumour breaks through the basement membrane of
the epithelium and the threat of local invasion, angiogenesis
and potential metastatic tumours develops. Fortunately,
almost all SCC cases encountered in the skin of horses are of a
less aggressive type at least in the early stages. There is little
tendency to metastasis even after aggressive local forms have
been allowed to develop. The one exception to this rule is
carcinoma of the conjunctiva in the medial canthus whether
associated with the nictitans or not. Recurrence at this site
following removal of even relatively small, benign and
innocuous looking tumours is extremely dangerous; often some
vascular or lymphatic (or both) invasion is reported from
histology even when a margin is considered to be safe. There is
Fig 5: a) and b) A severe burn case that healed extremely potential for metastatic spread to local lymphatic tissue; for
slowly over several years and in the end failed to heal the conjunctiva, caruncle and palpebrum, this is usually the
completely – it is easy to imagine that such a site could be
floor of the ipsilateral guttural pouch and then the pharyngeal
predisposed to carcinoma as a result of lack of pigment but
carcinoma development may be subtler than that. (Pictures give
lymph-nodes – both of these can of course be seen clearly
an opportunity to thank and pay respects to Aline Schunemann during guttural pouch endoscopy (Fig 8).
de Aluja, an outstanding contributor to the equine veterinary Unfortunately, there is still considerable disagreement or
profession). at least controversy amongst pathologists as to the best way
to classify this disease in a uniform and accepted manner
and so the literature remains confused and confusing. It is
carcinoma in all sites. The lack of a strong tendency to actually fortunate therefore that the more common forms of
metastatic transformation has given rise to a considerable squamous cell carcinoma occurring in the skin and in the
tolerance of the condition and that is probably something of conjunctiva in particular are only rarely metastatic. It is
a mistake since there is no doubt that if the tumour is left long important, however, always to examine the possibility of
enough, malignancy will develop both locally and potentially extension into a local lymph-node (where this is accessible)
at least, metastatically. The pathogenesis or progression/ (Fig 8) or into remote organs.
development of a carcinoma requires several important Equine SCC is not routinely graded by pathologists but a
circumstances. The “carcinogen” causes a minor genetic grading system has been suggested by several authors (Schuh
mutation resulting in hyperplasia. Under normal conditions 1986; Pe
rez et al. 1999; Van den Top et al. 2008a,b, 2010):
such a change would be arrested by cell cycle restriction
points that “carry out genetic quality control” before allowing • Grade I SCC - well-differentiated with numerous
the cell to complete the cycle of replication. The process of dyskeratotic cells and prominent keratin pearls, with
restriction and diversion of cells to the options of continuation obvious intercellular bridges
to replication, repair, diversion to a static (G0) cell or to • Grade II SCC - moderately differentiated with frequent
apoptosis are governed largely by complex relationships dyskeratosis but only occasional keratin pearls and poorly
within the cell. Viewed simplistically this process is controlled defined intercellular bridges
by the P53 family of genes. This and its associated cytokines • Grade III SCC - poorly differentiated cells with infrequent
and mediators therefore act as quality control mechanisms. keratinisation and some atypical mitotic figures and a high
Here lies one of the weakest points in the process of mitotic rate
carcinoma development. The p53 gene is seemingly
susceptible to UV light-induced mutation and indeed many These grades have been clinically and pathologically
other carcinogens, with consequent loss of function or associated with the depth of invasion in penile, cutaneous
aberrant function. Many studies have indicated that these and conjunctival carcinoma (Pe
rez et al. 1999). The grade

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4 Cutaneous squamous cell carcinoma

a) c)

b) d)

Fig 6: This horse sustained a relatively minor wound over the fetlock region some months previously. The wound appeared to heal
relatively normally for the first 3 or 4 weeks and then showed signs of abnormal “granulation tissue”. The wound was managed by
surgical debridement and a grafting attempt was made. Nothing responded at all (a) and ultimately a radiograph was taken to try to
identify possible causes of incipient wound healing failure (b). The underlying radiographs revealed extensive bone destruction and
tissue was then submitted for histology. This revealed a highly aggressive squamous cell carcinoma (c) with undifferentiated cells and a
high mitotic index (d) as shown in the histology slides here. Submission of all granulation tissue from nonhealing wounds for histological
examination can be clinically justified.

and presence of metastasis were not, however, linked in a • G3 (poorly differentiated): Anaplastic cells with other
study of oropharyngeal and nasal SCC (Schuh 1986). features that are more marked than those found in G2
A different grading system, based on the ratios of well- neoplasms including increased nuclear pleomorphism and
differentiated to anaplastic tumour cells, has also been higher mitotic activity (Fig 9c)
suggested (Van den Top et al. 2010). This is probably more
appropriate to the equine situation and is relatively easy to use. From a clinical perspective there is probably little to
• G1 (well-differentiated): SCC with only minimal basal/ choose between the various systems. Grading does give
parabasal atypia (Fig 9a) some indication of prognosis for penile/preputial SCC at
• G2 (moderately differentiated): A more disorganised least; higher grades are associated with reduced
neoplasm with less keratinisation, higher nuclear/ prognosis and increased risk of metastatic spread through
cytoplasmic ratios, thicker nuclear membranes, moderate lymphatic and haematological routes (Van den Top et al.
nuclear pleomorphism, occasional clumping of nuclear 2010). In the most malignant form micro-metastasis
chromatin, obvious nucleoli and higher mitotic rates probably occurs very early and is not always associated
(Fig 9b) with an apparently clinically aggressive primary tumour.

Fig 7: Diagrammative representation of the clinical and pathological events taking place during the progression of a squamous cell
carcinoma. It is important to realise, however, that this is a spectrum of change with no clear boundaries between the different ‘phases’
of development. Individual lesions will have variations in the appearance and the pathology. (Drawing by Vicki Martin).

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D. C. Knottenbelt and J. S. Croft 5

Development of squamous cell carcinoma

Squamous epithelia are found in
the skin, lining the respiratory tract,
Stratified squamous the lower urinary tract and parts
epithelial cells of the alimentary tract — including
the mouth, oesophagus and
Basement membrane squamous portion of the stomach.

Normal skin

Predisposing factors
Minor genetic ¥ Age (although any age affected)
mutation in a ¥ Non-pigmented skin
single cell Activation
¥ Chronic irritation or infection
¥ Cutaneous burns
¥ Poor wound healing Mutation
¥ Parasitic diseases may be
¥ Geldings > mares > stallions arrested
Ocular sites: chronic conjunctivitis, by genetic
chronic nasolacrimal duct quality
obstruction and eyelid deformities control
(role of Early
Causative factors p53 gene)
¥ Sunlight and other radiations detection
¥ Chemical exposure and
¥ Viruses Hyperplasia monitoring
Squamous dyplasia

Further genetic mutation?

Dysplasia

Mild Moderate Severe

Squamous papilloma Treatment

Further genetic mutation? potentially
curative
Lesions
can be Carcinoma
productive/ in situ
proliferative

or
erosive/
destructive

Carcinoma in situ Cutaneous SCC are

mostly less aggressive
Basement membrane with little tendency to
invaded Risk of
metastasis. However, local
SCC of conjunctiva at Invasive
medial canthus has high recurrence
cancer
risk of local recurrence after
and spread to ipsilateral resection:
gutteral pouch, then to long-term
pharyngeal nodes.
monitoring
essential

Invasive SCC
Spread via Spread via
lymphatics blood vessels
Metastasis

Treatment
futile but
palliation
sometimes
Secondaries in regional lymph Secondaries in organs unusual in horse, possible
Malignant SCC of sheath nodes more common in horse. with the exception of gastric carcinoma.
with extension to inguinal NB local lymphadenopathy SCC in respiratory and alimentary canals
and sub-iliac lymph nodes may be of inflammatory origin. can also become extremely aggressive.

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6 Cutaneous squamous cell carcinoma

a)
imparts a very characteristic grey or cream appearance to
the surface of the tumour (Figs 9a and 10a). This is usually
termed leukoplakia and this is one of the features of the
earliest types of preneoplastic or early neoplastic changes in
penile and conjunctival carcinoma in particular. Highly
destructive carcinoma is unusual but is more associated with
palpebral, clitoral and vulvar labial forms of the disease
(Fig 11). Many internal carcinoma lesions (such as the
pharyngeal, gastric and upper airway carcinoma) take on a
very aggressive local invasive and destructive behaviour; this
may be associated with avascular necrosis (the tumour
‘outgrows’ its own blood supply) but also local tissue
destructive mediators produced by both tumour and its
induced inflammatory responses.
Carcinoma tends to occur in older horses but there are
equally important predisposing and triggering factors than
age alone. Geldings are reported to be five times more
likely than stallions, and two times more likely than mares
to develop SCC. Penile carcinoma is rare in entire horses
b) but it does occur! Older geldings are more liable to SCC
of the penis and preputial skin than entire horses.
Nevertheless, penile carcinoma tends to be much more
dangerous when it occurs in the younger adult horse.
Mares may be affected by vulvar carcinoma and this
can be extremely aggressive in both progression and
malignancy (Fig 11).
Early diagnosis and intervention results in a cure in
many cases especially with the increasingly effective
chemotherapy systems now available. Although the clinical
diagnosis of carcinoma is usually relatively easy in most
cases of moderate or advanced carcinoma early lesions
often require further confirmatory tests. Early diagnosis is a
fundamental requirement for an improved prognosis –
usually the longer the tumour has been present, the poorer
the prognosis and the greater the therapeutic challenge.
Fig 8: a) This conjunctiva carcinoma had developed over many Biopsy provides the most definitive diagnosis; pathologists
months without any significant beneficial intervention. On can invariably make a diagnosis even in very early cases
examination, a secondary tumour was identified on (b): the floor and the addition of immunohistochemistry creates a
of the guttural pouch. Further examination revealed that the significant certainty of diagnosis. Cytological diagnosis from
retropharyngeal lymph-nodes were also involved. Clearly the
impression smears, fine needle aspirations or fluid samples
prognosis for this horse was extremely poor although local
extirpation and exenteration of the orbit could have resulted in at
from the peritoneal and pleural cavities may be useful but
least temporary palliative welfare improvement. sufficient numbers of exfoliated cells may not always be
present (Brazil 2008). For conjunctival and corneal
carcinoma lesions in particular, staining with Rose Bengal is
The most dangerous forms of SCC include the gastric a useful way to identify the extent and location of the
carcinoma, which has a rapidly fatal disseminating and tumours (Fig 12). Additionally, the lacrimal occult blood test
destructive course with haematogenous, lymphatic and is a sensitive but less specific test for ulcerative damage to
transcelomic spread. Carcinoma developing in the the conjunctiva (Fig 13).
alimentary or the respiratory tracts can also become The histological appearance provides excellent
extremely aggressive but most cutaneous forms are information regarding the degree of differentiation of the
fortunately far less liable to metastatic spread. cells and this is of significant clinical benefit both from a
Involvement of the first lymphoid “filter” is however prognostic and therapeutic perspective. The histological
relatively common. It is important to point out that local report should always contain information about the extent of
lympadenopathy can also be of an inflammatory origin; differentiation of the tumour cells and the integrity of the
usually, but not always, the node is then more painful basement membrane. The number of mitotic figures and the
than in neoplastic lymphadenopathy. degree of cellular atypia are key pathological features. The
The gross appearance of SCC masses varies significantly extent of vascular or lymphatic invasion also provides a good
between horses and different anatomical sites; some authors index for the prognosis (Fig 14). A summary of the suspec-
classify them as productive/proliferative or erosive/de- ted carcinogens, the prevalence and the clinical and
structive. The neoplasms are usually pale and firm due to pathological behaviour of the various forms of cutaneous
significant amounts of supporting fibrous tissue. Early well- carcinoma is shown in Table 1.
differentiated tumours often produce keratin and these are Of course, treatment is naturally the main focus of the
identifiable both clinically and histologically. The keratin clinical management. As might be supposed the earlier and

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D. C. Knottenbelt and J. S. Croft 7

a) Fig 9: a) Grade 1 SCC showing squamous dysplasia with

leukoplakia. This case illustrates the preneoplastic/dysplastic
state that is very characteristic of early penile carcinoma. These
grey or cream areas are termed leukoplakia and are largely due
to cellular hyperplasia of a mildly aggressive form that produces
significant amounts of keratin. That is the reason for the
appearance. From a clinical perspective, usually the keratin can
be peeled off from the surface in many of these lesions and this
will leave a slightly haemorrhagic mildly ulcerated surface. At this
stage the tumour is intraepithelial or in situ. b) Grade 2 SCC
showing proliferative changes with ulceration and infection. c)
Grade 3 SCC. This is a highly invasive, destructive carcinoma that
had extended to the inguinal and sub-iliac lymph nodes.

a)

b)

b)

Fig 10: a) A proliferative in situ (intraepithelial) carcinoma on the

nictitans. Notice the cream-grey pseudomembrane of keratin
c) and inflammatory debris covering the mass itself. b) Although this
in situ, intraepithelial carcinoma looks very bad, the large part of
the bulk of the tumour is made up of keratin. Of course, this is
somewhat unusual in the corneal epithelium because it is a non-
keratinising epithelium but this case does illustrate clearly the
cellular changes that occur in carcinoma in the early stages in
particular.

gold standard for carcinoma treatment but is not available

apart from in all but a few specialist centres (The
on et al.
1999; Hollis 2018). It can have dramatic and curative effects
(Fig 15).
the less aggressive the lesion the better the chances of a Leaving aside the challenges of internal SCC or
“cure”; this basic tenet of cancer medicine is perversely often metastatic SCC, there are opportunities to treat many
overlooked by horse owners. Radiotherapy is universally the cases effectively. The case described in this edition by

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8 Cutaneous squamous cell carcinoma

a)

b)

Fig 11: This highly destructive carcinoma of the vulva and clitoris
developed over a period of 8 months from a mildly erosive vulvar
labial carcinoma associated with the ventral labial margin and
clitoris. Delays and inappropriate treatment attempts resulted in a
hopeless prognosis.

Fig 12: a) and b) The diagnosis of SCC in these two cases was
not really equivocal but the use of Rose Bengal stain can be used
Poore et al. (2018) was treated with a combination of to add robustness to the diagnosis and confirm its extent. Notice
surgical tumour reduction and chemotherapy. In the case that they both show a characteristic ocular discharge.
described by Poore et al. (2018) an aqueous solution of 5-
fluorouracil was used at 2-week intervals. Although the
surgical pathology revealed an unsafe margin, the
concurrent use of a chemotherapy program resulted in
an apparent complete cure. The major point about this
was that the pathology was performed and acted upon!
The value of combined treatment methods cannot be
overstated (Plummer et al. 2007). The challenge in this
case is the possibility of metastatic development that may
only become apparent after some years (Mair et al. 2015)
or local recurrence which may also be very delayed; it
may look good enough for months or even years to give
a degree of optimism but the prognosis should always
remain guarded.
Surgical tumour reduction is an important principle of
cancer treatment and in some locations is highly effective
on its own (Mair et al. 2000; Payne et al. 2009). In effect,
the more tumour that can be removed, the less
Fig 13: The lacrimal occult blood test is useful and simple. A
adjunctive measures including topical or local intralesional
urine haemoglobin dipstick is gently touched onto the
chemotherapy has to do and therefore the less the doses accumulated tear drops and examined for blood positive
of chemotherapy required. If the whole tumour is remov- response. In this case an obvious carcinoma was present in the
ed with a clear margin there should be no necessity right eye but BOTH were positive. A small, early carcinoma was
for concurrent or adjunctive chemotherapy or radiation. present in the left eye conjunctiva at the lateral limbus.
The prognosis is, however, significantly improved when
chemotherapy is combined with sharp surgery, laser
surgical excision, cryosurgery or electrochemotherapy; a localised conjunctival carcinoma and a distal
results can be reasonably expected to be good. Examples phallectomy where a penile carcinoma involves the
of this include the removal of the third eyelid affected by urethral fossa and glans penis. Prospective or expected

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D. C. Knottenbelt and J. S. Croft 9

a) “safe margins” for skin tumours are usually established

from evidence-based reports but in the case of equine
oncology very little is known about any of the major
tumours so a sensible balance has to be drawn between
the two extremes of wide or narrow margins of excision.
The extent of safe margin is also important for local and
intralesional chemotherapy! Where a safe margin cannot
reasonably and confidently be identified or achieved,
concurrent measures can be justified. Surgery can also be
followed by cryosurgery or further surgery once the margin
has been declared unsafe and this might also have been
a choice for Poore et al. (2018) had chemotherapy not
been available or practical. Of course, removal of the
whole tumour locally does not mean that there is no
500 µm remote spread – that might have occurred a long while
b) previously. By the time a tumour is visible or palpable, it is
usually around 66% of its natural lifespan so events may
well have taken place before this point.
Squamous cell carcinoma is generally sensitive to many of
the available chemotherapy agents (Knottenbelt et al. 2015).
Since margins are impossible to define in most cases anyway
and since the tumours can be microscopic and infiltrative,
chemotherapy is often a sensible adjunctive treatment.
Poore et al. (2018) instigated the chemotherapy with
repeated aqueous 5-fluorouracil immediately after the
surgery; this is always the pragmatic option to maximise the
prognosis. A slow release method based on an emulsion of
cisplatin, carboplatin or 5-fluorouracil with sesame oil has
been used successfully by several previous authors including
The
on et al. (1999) and could probably have been useful in
the case described by Poore et al. (2018). Reported case
series using intra- or peri-lesional chemotherapy in slow
release emulsions have been uniformly impressive.
Additionally, topical aqueous mitomycin C has been used
also to good effect in conjunctival carcinoma (Malalana
c) et al. 2010).
Topical chemotherapy on its own can also be effective
(Patterson 1997; Malalana et al. 2010) provided that cases
are suitably chosen but surgical tumour reduction is an
effective way of hastening the resolution and enhancing the
overall prognosis. Rayner and van Zyl (2006) described the
use of topical mitomycin C and achieved a 90% success rate
as measured by nonrecurrence at 11 months post treatment.
Malalana et al. (2010) compared the topical mitomycin C
chemotherapy with and without concurrent surgery and
concluded that the surgical/chemotherapy option was more
likely to result in a cure.
Electrochemotherapy using cisplatin has been used to
manage a variety of cutaneous tumours without concurrent
surgery and high success rates are reported (Cemazar et al.
2008).
Systemic chemotherapy is in theory at least possible but is
not widely practiced and in any case with focal tumours
affecting single organs or structures it is probably
unnecessary. Nevertheless COX-2 inhibitors such as
Fig 14: Three different types of carcinoma. a) This proliferative meloxicam or piroxicam can be justified especially if the
carcinoma of the nictitans illustrates the intraepithelial (in situ) tumour COX-2 expression can be confirmed by
nature of this tumour type. There are keratin pearls shown here as
immunohistochemistry. Daily oral doses of 80 mg of piroxicam
well (arrows). The solid head arrow is the corneal stroma. b) A
histological section of a cutaneous carcinoma with well-
(regardless of the size of the horse) have been reported to be
differentiated cells and obvious keratin “pearls”. c) An helpful (Moore et al. 2003; Iwabe et al. 2009). Piroxicam
undifferentiated penile carcinoma with no obvious keratin, mitotic reduces both direct DNA damage and malignant
figures and an invasive nature. (Pictures courtesy of Lorenzo transformation of cells. It also promotes apoptosis in tumour
Ressel [a] and Janet Patterson Kane [b; c]). cells and has a positive effect on cancer cell immunity by

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10 Cutaneous squamous cell carcinoma

TABLE 1: The prevalence, suspected carcinogenesis, type and pathological behaviour of SCC at various cutaneous sites

Pathologic/clinical behaviour

Location Prevalence Predisposition/carcinogens Proliferative Invasive Malignancy

Eyelids/conjunctiva +++ Depigmentation + ++++ +

Sunlight (UV)
Cornea (in situ carcinoma) + Sunlight (UV) +
Lips and facial skin + Sunlight +++ ++++ ++
Repeated minor injury
Contact agents
Vulva/clitoris ++ UNKNOWN +++ ++++ ++
Smegma
Penis/prepuce +++++ Depigmentation ++ +++++ +++
Smegma
SKIN ++ Sunlight (UV) +++ +
Contact/chemical
Burn sites
Wound sites

reducing prostaglandin E2 expression by neoplastic and other remember that carcinoma at any site including those
cells. Additionally, it suppresses cellular proliferation and affecting the conjunctiva and the skin can sometimes
inhibits angiogenesis. It is probably a worthwhile addition to recur after a much longer period (Elce et al. 2011).
the management of all SCC cases no matter what other Additionally, and importantly from a prognostic per-
treatment is employed although it would be helpful to spective, distant spread in the absence of any local
establish the COX-2 expression first. It may be a significant aid evidence of tumour recurrence can be recognised much
to long-term survival. later (Mair et al. 2015). Regular, careful and detailed
Other treatments that have been reported include monitoring of all patients is essential and especially
photodynamic therapy, cryosurgery and immunotherapy when vascular and lymphatic invasion and an unsafe
(Arnold et al. 2017). New methods including immunotherapy margin are reported from the surgical pathology. The
using dendritic cells and other mediator driven approaches pathology, whether from biopsy or from surgical (excisional)
are being explored and may have some future (Arnold et al. pathology is very important and should never be
2017). overlooked and especially not on economic grounds; it is
It is clear that SCC is an eminently treatable tumour in counterproductive, unwise and unprofessional.
most cutaneous sites provided that the condition is The challenges of chemotherapy were also raised by
diagnosed early and pursued relentlessly to elimination. Poore et al. (2018); they noted the need to protect the
There are many different approaches that can be made operators and the handlers of the horse from inadvertent
and it is time that extensive multicentre studies were contact with drugs at the site of the procedure and in the
carried out to compare the various treatment options urine and droppings. It is important to remember that every
rather than reliance upon small case series or individual chemotherapy agent will have some pro-mutational effects;
cases. exposure of humans to the drugs could be considered an
The long-term prognosis for all forms of carcinoma unacceptable hazard. The principle of ALARA (as low as
depends on both local recurrence and distant metastasis. reasonably achievable) for exposure to chemotherapeutic
Local recurrence usually reflects a failure of clinical agents is no longer acceptable. There should in fact be no
management or, in surgical cases a failure to explore the exposure at all if proper protection is afforded. Operator and
possibility of an unsafe margin of excision. The lack of a handler safety is paramount and anyone using these
safe margin and the extent of both lymphatic and chemicals must take special care to ensure human
vascular involvement have to be considered in every and environmental safety as well as safe disposal of
case. However, since an exhaustive absolutely certain safe all contaminated materials. Special disposal systems for
margin can seldom be guaranteed by a pathologist, it is chemotherapeutic and hazardous waste are obligatory.
wise to be careful when advising owners of the prognosis. Perianal carcinoma is very rare in horses but it clearly
In addition, carcinoma can seed into an operative site does occur and although no particular carcinogen can be
from the surface of an exposed ulcerated carcinoma suggested, any proliferative or ulcerated lesions in this region
during surgery; this cannot of course be identified by a should be carefully examined. Since SCC is commoner in
pathologist examining the surgical specimens. The biggest older horse (Valentine 2006), the advanced age of the horse
mistake that can be made during treatment is to ignore in the case described by Poore et al. (2018) may have
the surgical pathology! The safety of excisional margins is played some part in its aetiopathogenesis. The correct
so important that every excised tumour no matter how choice of treatment is imperative and the best available
“certain” the excision might seem, should be submitted for combination method should always be employed.
examination; this should not be regarded as an ‘optional Concurrent chemotherapy following any surgical tumour
extra’! reduction is a sensible option (Fig 16). Fortunately, metastatic
The case described by Poore et al. had a 6-month spread from cutaneous SCC (apart from some preputial and
local disease free follow-up and it is important to penile forms) is uncommon although the first lymph node in

© 2018 EVJ Ltd

D. C. Knottenbelt and J. S. Croft 11

a) a)

b)

b)

c)

c)
Fig 15: SCC is very sensitive to b or c radiation. The former is
usually limited to corneal carcinoma in situ using strontium96
wand plesiotherapy. The latter is conventionally carried out
using high or low dose intralesional iridium192 or gold198
brachytherapy. This destructive carcinoma developed in the
nasal half of a pigmented lower eyelid. It was treated using low
dose brachytherapy with iridium192 and showed a very satisfying
and total resolution. The lower right picture was taken at 6 weeks
post treatment and the full effect took around 9 months; no
recurrence occurred in spite of the pigment loss since the owner
was advised to keep the horse out of strong sunlight.

Fig 16: Top: This massive proliferative and invasive carcinoma of the
clitoral sinus and vulvar labiae. Middle: It was removed surgically.
Bottom: Adjunctive slow release 5 fluorouracil emulsion in sesame oil
was infiltrated using a preplanned orthogonal set of 19 g needles.
The process was repeated 5 times at 2-week intervals and resulted in
a satisfactory resolution – at least in the short term. Long-term follow-
up is not available. (pictures courtesy Heather Armstrong)

© 2018 EVJ Ltd

12 Cutaneous squamous cell carcinoma

the chain can be affected. Recurrences and metastasis Mair, T.S., Walmsley, J.P. and Phillips, T.J. (2000) Surgical treatment of
can become clinically evident months or even years after 45 horses affected by squamous cell carcinoma of the penis and
prepuce. Equine Vet. J. 32, 406-410.
apparent local resolution and monitoring is essential. EARLY
DIAGNOSIS is a fundamental requirement in cancer medicine Mair, T.S., Sherlock, C.E. and Pearson, G.R. (2015) Delayed metastasis
of ocular squamous cell carcinoma following treatment in 5
and every opportunity should be taken to screen horses, horses. Equine Vet. Educ. 27, e9-e14.
clinically at least, as often as possible.
Malalana, F., Knottenbelt, D.C. and McKane, S.A. (2010) Mitomycin C,
with or without surgery, for the treatment of ocular squamous cell
Authors’ declaration of interests carcinoma in horses. Vet. Rec. 167, 373-376.
Moore, A.S., Bean, S.L., Rassnick, K.M. and Provost, P. (2003) Long term
No conflicts of interest have been declared. control of mucocutaneous squamous cell carcinoma and
metastases in a horse. Equine Vet. J. 35, 717-718.

Ethical animal research Patterson, S. (1997) Treatment of superficial ulcerative squamous cell
carcinoma in 3 horses with topical 5-fluorouracil. Vet. Rec. 141, 626-628.
Not applicable. Payne, R.J., Lean, M.S. and Greet, T.R.C. (2009) Third eyelid resectionas
a treatment for suspexcted squamous cell carcinoma in 24 horses.
Vet. Rec. 165, 740-743.
Source of funding Pazzi, K.A., Kraegel, S.A., Griffey, S.M., Theon, A.P. and Madewell, B.R.
None. (1996) if Analysis of the equine tumour suppressor gene p53 in the
normal horse and in eight cutaneous squamous cell carcinomas.
Cancer Lett. 107, 125-130.
Authorship
rez, J., Mozos, E., Martin, M.P. and Day, M.J. (1999)
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Immunohistochemical study of the inflammatory infiltrate
Both authors have been involved in the preparation, writing associated with equine squamous cell carcinoma. J. Comp.
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