5 Oct 2015
Sublingual squamous cell carcinoma in a nine-year-old, female neutered, domestic short-haired cat.
Squamous cell carcinoma (SCC) is the most common tumour affecting the oral cavity in cats (Cotter, 1981).
Feline oral SCC (FOSCC) is a locally aggressive tumour with a low metastatic rate, reported in one study as 14.8% to the lymph nodes (Marretta et al, 2007).
The development of FOSCC is unknown, but some factors have been linked to increased risk of this type of cancer.
In human head and neck SCC, papillomavirus is considered an important risk factor as well as tobacco smoke and alcohol consumption.
Cats living in households with smokers are considered more at risk of FOSCC compared to those in non-smoking homes (Bertone et al, 2003; Snyder et al, 2004). This is possibly due to the deposition of chemicals from tobacco smoke on the coat, in conjunction with grooming habit.
This grooming habit could also explain the increased incidence of FOSCC in cats exposed to flea collars (Bertone et al, 2003).
The same study reported cats with high canned food intake in their diet are at greater risk of developing SCC.
The relationship of papilloma virus to FOSCC is not well established, but in one study 90% of feline cutaneous SCC carried papillomavirus DNA (Munday et al, 2008).
The prognosis for FOSCC is guarded to poor. It is often not detected or presented until it has reached an advanced stage, by which time the possibility of complete surgical excision is low.
The survival rate of cats with FOSCC treated palliatively in general practice is low – reported to be 44 days in one study (Hayes et al, 2007).
Surgery alone is rarely curative because of the size and location of the tumour (Bradley et al, 1984).
The median survival time is around three months for SCC-invading sites other than the mandible (Bradley et al, 1984).
Improved survival times of around five-and-a-half months may be achieved when the tumour is localised to the mandible and mandibulectomy is performed (Northrup et al, 2006).
In one study the combination of mandibulectomy and radiation therapy resulted in a median survival of 14 months (Hutson et al, 1992).
Non-resectable FOSCC responds poorly to radiation alone (Cotter, 1981).
Many studies have reported using radiotherapy with palliative or definitive intent, but survival times showed little to no improvement.
In a study of seven cats treated with palliative radiotherapy at days zero, seven and 21, the overall median survival was reported as only 60 days (Bregazzi et al, 2001).
A more traditional radiotherapy regimen of 3gy to 4gy, delivered over three weeks to four weeks, was not effective in controlling the local disease either (Postorino et al, 1993).
Accelerated and hyperfractionated radiotherapy has been proposed as a treatment. This seems more beneficial in head and neck SCC in human patients (Horiot et al, 1997).
Accelerated radiotherapy delivers the same total dose in less time. In theory, this approach should reduce the regrowth of the tumour between fractions (treatments), resulting in improved local control of the disease.
The regimens consist of two to three fractions delivered each day, with a reduced dose per fraction. The latter may reduce the risk of late toxicity and allow an increased total dose leading to greater efficacy.
An accelerated radiation protocol has been used in cats to treat advanced SCC. Nine out of 10 cats treated with 3.5gy for a total of 49gy in a nine-day period had FOSCC, but again the median overall survival was poor – 86 days.
Whichever treatment protocol is used, radiotherapy alone has not been found to improve survival.
Chemotherapy alone has also been ineffective in controlling the disease.
In one study, a liposomal-encapsulated platinum compound, cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) (L-NDDP), was administered IV every 21 days.
An average of two doses was administered, but none of the cats had a complete or partial remission and median survival was only 59.8 days (Fox et al, 2000).
In one study, palliative radiotherapy was combined with low dose gemcitabine as a radiosensitiser in eight cats.
Gemcitabine was administered at 25mg/m2 twice weekly, with six doses of 6gy radiotherapy to a total dose of 36gy (Jones et al, 2003).
Despite a small improvement compared to radiotherapy alone, the median survival was still only 111.5 days.
In a more recent study, 31 cats were treated with accelerated 14 fractions of 3.5gy across nine days, with carboplatin also given at between 90mg/m2 and 100mg/m2 on day one and day 4.5. The median survival was 163 days. However, severe side effects were reported, necessitating the placement of a feeding tube in 78% of patients (Fidel et al, 2011).
A pilot study reported a multimodal approach including surgery, medical treatment and radiation therapy in six cats, with encouraging results.
Three of the cats were alive and in remission at the close of analysis, of 759, 468 and 362 days respectively (Marconato et al, 2013).
In the absence of an effective treatment, palliative management with anti-inflammatory drugs is often used.
In particular, NSAIDs may not only have anti-inflammatory and analgesic properties, but specific anti-tumour effects by preventing cyclooxygenase-2 (COX-2). COX-2 is important in tumour development, growth and neovascularisation.
COX-2 has been found expressed in up to 67% of FOSCC, but no correlation with survival has been found (Hayes et al, 2005).
In one study where most of the patients were treated with NSAIDs, the median survival was only 44 days (Hayes et al, 2007).
In human medicine, superficial oral SCC has been treated successfully using photodynamic therapy (Copper et al, 2003).
The therapy uses a photosensitiser that accumulates in the tumour cells. After illuminating the tumour with light of the correct wavelength, the photosensitiser absorbs the energy to induce the production of reactive oxygen species that kill the tumour cells.
Photodynamic therapy has been used in veterinary medicine, especially in cats with superficial SCC of the nose with good results (Stell et al, 2001; Bexfield, 2008).
Efficacy and tolerability of this treatment for FOSCC has not yet been investigated.
An immunohistochemical study looked at possible prognostic indicators and explored future targeted therapy.
Epidermal growth factor receptor (EGFR) is a tyrosine kinase transmembrane receptor that controls important pathways in cancer growth, invasion, metastasis and cancer neovascularisation.
EGFR was found expressed in 69% to 100% of FOSCC cases, but the correlation with survival was unclear (Bergkvist et al, 2011; Yoshikawa et al, 2012).
Mitotic index (MI), which measures the average of mitoses per 10 high power fields, has been widely used to assess and quantify the growth rate of tumours.
It is a useful proliferation index, but is subjective to the pathologist’s counting. Also, the values in different portions of the sample can vary.
A more objective index is Ki67, a nuclear protein expressed in dividing cells. Higher Ki67 values correlate with an increased tumour growth rate and metastatic risk in many cancers in humans and other domestic species.
This proliferation marker has been used in veterinary medicine in particular for mast cell tumours (MCT), where high values correlate with poor survival.
High Ki67 values correlated with decreased FOSCC survival in one study (Bergkvist et al, 2011). However, another study found no correlation with MI and Ki67 and survival.
The overexpression of Ki67 and its relationship with FOSCC survival remains controversial (Yoshikawa et al, 2012).
FOSCC is a locally aggressive tumour and, despite the efforts of veterinary oncologists, radiotherapists and surgeons, the prognosis for non-resectable FOSCC is very poor.
Location is an important factor. FOSCCs under the tongue are most difficult to approach surgically and carry the worst prognosis. Unfortunately, most FOSCCs are in this location.
Improvements in survival with multimodal therapy are encouraging, but such studies are based on very few cases and difficult to interpret.
Furthermore, this aggressive approach is often difficult to justify because the mild improvement in survival may be outweighed by high costs and stress for the owner and the patient.
Advances in cancer research have resulted in recognition of cell signalling pathways aberrantly activated in cancer cells.
Drugs used to target these pathways or key receptors are already in use for human and veterinary species (for example, masitinib and toceranib).
The Wnt pathway plays a key role in cancer (Polakis, 2007; Wang et al, 2010; Thrasivoulou et al, 2013).
Researchers at University College London have proposed a therapy based upon the inhibition of the Wnt signalling pathway by calcium channel blockers. Preliminary results show increased expression/deregulation of this pathway in squamous cell carcinomas.
The authors are interested in using a calcium channel blocker in lingual or advanced oral feline SCC, when no other treatments are available.
The proposed drugs are off-label and have minimal to absent side effects. They have been in clinical use for other indications in human and other animal patients, including cats, for many years. The cost of the proposed therapy is minimal.
The authors would appreciate help collecting cases of FOSCC. They are also developing a protocol for the treatment of FOSCC with photodynamic therapy and are happy to discuss this approach. Email [email protected]
