Cutaneous squamous cell carcinoma in the cat

Squamous cell carcinoma (SCC) accounts for 15-20% of cutaneous tumours of the cat._^20,21 It is one of the most common skin neoplasms in this species and occurs mainly on the head, although cases can also be observed on the limbs and, more rarely, on the back, abdomen, tail and perineal region (Fig. 1). A now accepted risk factor is a pale coat and a lack of hair in areas greatly exposed to sunlight, such as the head. Black cats and Siamese cats, like other pureblood breeds, are affected very rarely. It is now certain that sunlight is involved in the pathogenesis of these tumours, as demonstrated by the fact that white cats have a 5- to 13-fold higher risk of developing skin tumours than have cats with a dark coat._⁹ The type of tumour induced by solar irradiation is known as actinic squamous cell carcinoma

The mean age of onset is fairly high (12 years), although younger cats can be affected by pre-malignant lesions that can evolve over months or years. A gender predisposition has not been described, whereas there does seem to be a correlation with positivity for feline immunodeficiency virus (FIV), although this correlation could be due to the common risk factor of an outdoor life, which exposes the cat to both a greater risk of infection by the virus and to greater exposure to ultraviolet radiation.

In its initial (pre-malignant) stage, SCC is manifested as shallow, crusted lesions that are painless and evolve slowly; these are often mistaken by the animal’s owner as scratches that are failing to heal (Fig. 2). For this reason, months or even years may pass before the problem is brought to the attention of a veterinarian.

There are two pre-malignant conditions, called actinic keratosis or carcinoma in situ, and pre-neoplastic dermatitis or Bowen’s disease, which can remain as such for years or evolve into a more invasive disease. The former generally appears as a solitary lesion in scarcely pigmented areas exposed to the sun, such as the ears, temporal regions, eyelids and nose, above all in white cats. Bowen’s disease, on the other hand, appears as multiple, usually small lesions that are plaque-like, well-demarcated, pigmented and partially alopecic; these lesions, which are not painful or itchy, develop on both the head and neck and on the limbs._^11,23 Bowen’s disease is not always related to exposure to ultraviolet rays (Fig. 3).

As already mentioned, it is now clear that sunlight is involved in the pathogenesis of SCC of the head in the cat. Furthermore, overexpression of protein p53 has been demonstrated in a high percentage of feline cases of SCC of the head,_^11,31 indicating that changes in this protein can promote the appearance of the tumour in cats, as it does in other species such as humans and cattle. Recently, Bardagi et al. (2012) found that cyclo-oxygenase-2 (COX-2) is overexpressed in many samples of feline and canine cutaneous SCC;_⁴ this contrasts with a previously reported observation by Beam et al. (2003),_⁵ who found positivity for COX-2 in only a small percentage of cases of oral SCC in the cat and in no cases of cutaneous SCC. The authors did, however, comment that this could have been due to the poor sensitivity of the detection system they used. The study by Bardagi et al.,_⁴ therefore, seems more reliable; the authors reported that positivity for cyclo-oxygenases was found in both specimens of actinic keratosis and of SCC, particularly in the vicinity of ulcerated and inflamed areas. Their hypothesis is that COX-2 is produced by the tumour and can subsequently facilitate infiltration by inflammatory cells. The fact that ultraviolet B rays significantly increase the expression of the COX-2 gene in humans and mice_¹ seems to add further support to the pathogenic correlation between exposure to sunlight and the development of SCC.

Another factor recently suggested to be involved, at least in part, in the development of feline SCC is infection by viruses of the Papillomavirus (PV) family. Nespeca et al. (2006)_²³reported the presence of a variant of feline PV in skin biopsies from sites not exposed to sunlight in cases of both SCC and Bowen’s disease, whereas the viral sequences were not present in normal skin samples. Another study_²² demonstrated the presence of PV in 100% of the samples of skin taken from cats with Bowen’s disease and in 85% of those from animals with invasive SCC, but in only a small percentage of specimens of non-malignant lesions, leading the authors to suggest that there is a correlation between PV and SCC, but that other elements are needed to demonstrate that the virus is able to promote the malignant transformation. In support of this theory, it has been shown that the viral infection can prevent the repair of damage to DNA induced by sunlight and the consequent apoptosis of cells. Other studies have found PV of non-feline origin in the squamous cell lesions of the cat, which could indicate the possible passage between species of viruses of the same family._^2,11,24

CLINICAL PRESENTATION AND DIAGNOSIS

Cutaneous SCC presents initially as crusty lesions which, in 80-90% of cases, involve the head and, in particular the pinnae, the nasal planum, the eyelids and the temporal regions. The palpebral lesions are often associated with lesions in other sites. In about 10% of the cases the tumours develop on the skin of the abdomen, limbs, back, tail and perineum; in these cases, the involvement of solar irradiation is much less probable._²¹ In 30% of cats the lesions of the head are multiple (Fig. 4). The evolution is very slow and the lesions are often undervalued by the owner, who thinks that they are scabs following scratches, considering that the affected animals frequently spend some of the time outdoors. These lesions, often only actinic keratosis or Bowen’s disease, must not be neglected by the clinician, since the treatment of superficial lesions is associated with a much better prognosis than that of the more invasive forms. Unfortunately, it is not a rare occurrence to examine an animal for the first time with very advanced stage lesions of the ear or nasal planum (Fig. 5). This happens because the tumour is not painful and does not debilitate the animal until the terminal stages, despite the marked invasiveness, and because of the slowness of the development of metastases, which appear late and mostly involve the regional lymph nodes and only rarely the lungs.

The diagnosis and staging are, however, fairly simple; the differential diagnoses, particularly for the nasal lesions, include immune-mediated or traumatic lesions and other rarer tumours such as lymphoma, melanoma, haemangioma and eosinophilic granuloma._³⁴ SCC can present as a proliferative form (less common in the cat), characterized by the presence of reddish plaques and cauliflower-shaped excrescences which lead to the formation of ulcers, and as an ulcerative form, characterized by scabs covering reddened areas of erosion that progressively evolve into deep, disfiguring ulcers.

The diagnosis is based on information from the past clinical history (persistent scabs), clinical examination of the lesion and regional lymph nodes, a complete blood count and a biochemistry screen to evaluate the general condition of the cat (in view of therapy) and tests for FIV and feline leukaemia virus. A chest X-ray is not strictly necessary for staging purposes,_¹⁸ given that lung metastases are very rare and usually late, but it is good practice to perform one, since these are elderly animals which  may have to undergo a general anaesthesia, so evaluation of the lungs could provide useful information on the animal’s general state. In contrast, a fine needle biopsy of the regional lymph nodes is very important if these are enlarged and/or hardened. Cytological examination of material acquired by apposition of slides on the cutaneous lesions is not recommended since the findings are almost always those of an inflammatory process, secondary to the lesion which could, therefore, be under-diagnosed. Deep scarification with a scalpel blade and collection of the material obtained can yield better results. Fine needle biopsy (preferably with a small bore needle) can provide useful results when the lesion is proliferative or invades deep tissues. The diagnosis is, however, confirmed only by histological examination, which should always be performed when the cytological examination shows an inflammatory process and in all cases that cytological studies are not possible. The simplest way to obtain a sample for histological examinations is to carry out a small incisional biopsy with a scalpel blade or (for example, for lesions of the nasal planum) a punch biopsy. It is important to obtain a full thickness sample of the skin since this provides information on the extension of the disease, which is extremely useful for prognostic purposes (Table 1). As demonstrated by Favrot et al. (2009),_¹¹ the histological distinction between actinic keratosis and Bowen’s disease is not always easy, but both lesions should, in any case, be considered pre-malignant and treated accordingly.

Table 1. Owen’s staging system for SCC of the skin (1980). The information on the tumour (T) is combined with that on the lymph nodes (N) and distant metastases (M).

As shown by the staging system reported in Table 1, the factor that influences the prognosis most strongly is the extent of invasion of the deep tissues; indeed, although it is uncommon to see lesions with a diameter of more than 5 cm in a cat, the lesions have very often already invaded the subcutaneous layer and are, therefore, considered as T₃, even if small.

The possible therapeutic strategies to adopt are based on the stage of the tumour and the clinical condition of the cat.

TREATMENT

There are numerous therapeutic options for cutaneous SCC in the cat, but the possibility of a real cure is dependent above all on the earliness of the diagnosis and, therefore, the invasiveness of the lesions.

For actinic keratosis, Bowen’s disease and SCC stages T_is to T₂ all options give good results, although surgical excision is often the simplest and most curative method. In particular, ear cropping (Fig. 6), as well as the excision of lesions on the trunk, is simple, quick to perform and the surgical wound heals easily.

The surgical removal of a carcinoma of the eyelids, together with the tumour margins, is more complex and plastic surgery is required to reconstruct the defect created_^3,16,27 (Fig. 7).

Excision of nasal lesions can be seen by owners as particularly disfiguring, but is generally well tolerated by the animal, even if the first few days after the operation can be a bit challenging because of the scabs that form at the site of surgery, which can interfere with breathing._³⁵

Once the first few days of discomfort have passed, the functional and cosmetic results are good (Fig. 8). The same cannot be said for the oncological result, since the particular anatomical site makes it difficult to obtain tumour-free margins unless the lesion is very superficial. For this reason in the case of advanced tumours care must be taken in selecting the patient and planning the therapy, which may involve the use of other forms of treatment, apart from surgery.

Photodynamic therapy is a valid option for many superficial, small SCC or pre-neoplastic lesions. Although general anaesthesia is necessary in order to administer this therapy, a single session is usually sufficient to obtain the desired result. Various photosensitising agents are available for both topical use and intravenous administration depending on the active ingredient and the wavelength of the light source used for the radiation. In one study³⁰ the complete remission rate of stage T_is - T₁ lesions was 85% following the use of a topical photosensitiser (5-aminolaevulinic acid), although recurrences occurred in 63.6% of the subjects within a median time of 21 weeks. Using the same agent, Bexfield et al. (2009)_⁶ obtained a similar rate of complete responses but a local recurrence rate within 28 weeks of 51% and 45% of the cats were alive after a median of 1146 days. The use of a new photosensitiser carried in liposomes and administered intravenously a few hours before exposure to a light of appropriate wavelength led to a complete response rate of 100% as well as a decrease in the local recurrence rate to 20% at 24 weeks and to 75% at the 1-year follow-up._⁸ The advantage of this technique, besides the excellent cosmetic result (Fig. 9), is that it can be repeated several times in the case of recurrence or lack of achievement of complete response. With respect to surgery, this technique has the disadvantage (shared by all non-surgical treatments) that the margins of the area treated cannot be evaluated; furthermore, the animal must remain out of sunlight for several days after the treatment.

Another local treatment useful for early stage lesions is the local infiltration of chemotherapeutic agents; the most widely used agents are bleomycin and platinum-containing compounds, which can also be combined with radiotherapy as radiosensitisers. In a study in which this association was used,_¹⁰ the response rate was 100% and the median follow-up was 268 days. Cisplatin is highly toxic and is not used systemically in the cat, but can be administered locally without any problems. General anaesthesia is, however, needed in this case because the infiltration is very painful and the treatment must be repeated several times to be effective. One reported protocol involved eight applications, carried out once weekly for the first four applications and then every fortnight for the next four applications (Fig. 10). The drug is administered through a small calibre needle in a centripetal manner around the lesion, including a few millimetres of macroscopically healthy tissue.

Using this method to infiltrate carboplatin at a dose of 1.5 mg/cm_³ of lesion, Théon et al. (1996)_³³ obtained complete responses in 73.3% of animals, but recurrences occurred in seven of the 15 cats treated. In order to increase the local permanence of the drug it was suggested delivering it with substances acting on the local blood vessels (e.g., adrenaline combined with bovine collagen),_¹⁷ which would increase local inflammation, and with substances favouring slow release of the drug (sesame oil)_³³ or binding it (autologous serum). Subsequent studies²⁸ demonstrated that the plasma protein binding of carboplatin is less than that of cisplatin, and thus, increasing the volume inoculated by binding it to autologous serum is only justified in the case of cisplatin, but not when carboplatin is used. The limitations of local infiltration, besides it requiring repeated anaesthesia, are related to the invasiveness of the tumour, the poor penetration of the chosen drug in tissues and its dispersion in the environment for a period difficult to quantify but with the consequent risk, albeit minimal, of harm to people administering the drug and those handling the animal after the treatment.

In order to avoid this problem and improve the intracellular penetration of the drug, electrochemotherapy_⁹ can be used. This technique consists of administering an electrical stimulation, through a device with a series of needles, into the site of the tumour after topical or systemic delivery of a chemotherapeutic agent (usually bleomycin or platinum-containing compounds). Although this technique may have to be repeated several times, with general anaesthesia, its results appear promising.

Systemic chemotherapy with the same drugs as those administered locally is rarely used because the response is not particularly good and control of metastases is not the main problem with this type of tumour; furthermore, positivity for FIV, present in a fair percentage of cats with SCC, makes the side effects of systemic chemotherapy more severe and more difficult to control.

Radiotherapy with orthovoltage or megavoltage equipment produces good results, particularly in lesions that are not too advanced. Thèon (1995)_³² reported a cure rate of 56% at 5 years for cats with stage T₁ lesions treated with orthovoltage radiotherapy, while more recently a complete response rate of 60% was reported_¹² in animals with stage T₁ lesions treated with proton radiotherapy, compared with 33% in cats with stage T_2b lesions (that is, invasive lesions with a diameter > 1.5 cm), and a median survival of 946 days. Melzer et al. (2006)_¹⁹showed a positive correlation between response to radiotherapy and strong positivity for Ki67, an index of cell proliferation usually associated with a worse prognosis; this is probably because rapidly proliferating cells are more sensitive to treatment. The complete response rate in this study was 94%, while six of the 17 cats had recurrences within a fairly short time (21-414 days); the median disease-free survival was 414 days. In this study, the histological grade did not appear to be an important prognostic factor (Fig. 11).

A more superficial form of radiation therapy, suitable, therefore, for early stage lesions, is plesiotherapy with _⁹⁰Strontium, which consists of placing the radioactive source in direct contact with the lesion. In a study of 15 cats with SCC of the nasal planum treated with this type of therapy, 11 (73%) achieved a complete response after the first cycle of five applications (total dose, 50 Gy), while the remaining four (27%) had a partial response: two of these animals underwent a second treatment cycle, which induced a complete response in both. The median disease-free survival was 652 days._¹⁴ The animals in this study did not have lesions beyond stage T₂. The side effects of this technique are minimal. Although its use is limited by the depth and spread of the disease, thus requiring a careful patient selection, both the oncological and the cosmetic results are good. Even more encouraging results have been published by Hammond et al.,_¹⁵ who obtained complete responses from using a single administration of radiotherapy in a series of 49 cats; the median progression-free survival was 1710 days.

A therapeutic option for very superficial lesions is topical treatment with a cream containing imiquimod 5%._^13,25 Topical treatment of 12 cats with multiple lesions, to which the cream was applied once a day or three times a week, led to an initial response in all subjects although 75% subsequently developed new lesions. All but one of the cats were treated lifelong and the median time to disease progression was 243 days, while the median survival was 1189 days. Peters-Kennedy et al._²⁵ reported a good outcome for a cat given topical treatment for lesions of the pinna, but a poor result in the same animal for a lesion on the nasal planum. Erythema occurred in all cases and systemic side effects sometimes imposed a modification of the administration regimen.

Other techniques that have been used, with variable results depending on the extent of the pathology, are cryosurgery, laser therapy, heat treatment and oral administration of retinoids.

PROGNOSIS

Although feline SCC of the skin is a malignant disease, its course is fairly slow and years can pass between the appearance of the pre-neoplastic lesions and death. Some factors have a degree of prognostic value. These include the histological grade of differentiation of the tumour⁷ (the greater the differentiation, the better the prognosis), positivity for epidermal growth factor receptor (associated with a worse prognosis),_²⁶ and a high concentration of vascular endothelial growth factor (associated with a worse prognosis),_⁸ while the mitotic index does not seem to be a prognostic factor. Strong positivity for Ki67, an index of cell proliferation, was associated with a longer disease-free period and a better response to accelerated electron beam radiotherapy in another study._¹⁹ The extent of the tumour, intended particularly in terms of its local invasiveness (the T of the TNM staging) is a negative prognostic factor: as the T increases, the response to therapy decreases.

Positivity for FIV, on the other hand, is not a negative prognostic factor in an absolute sense, but it can worsen the side effects of the treatments administered.

PREVENTION

As is often the case in veterinary practice, the best form of prevention is early diagnosis. In this particular case, the diagnosis and treatment of pre-malignant lesions is easy and offers a good possibility of cure or long-term disease control. It is, therefore, important to educate owners not to undervalue the problem, especially in predisposed animals, such as in pale-coated cats. In such cases it is useful to limit direct exposure to sunlight, although this is difficult to achieve if the cat lives outdoors. The use of total barrier creams is more theoretical than practical, as is the possibility of tattooing areas of skin at greatest risk.

References

1. An KP, Athar M, Tang X et al. Cycloossigenase-2 expression in murine and human non-melanoma skin cancers: implications for therapeutic approaches. Photochem Photobiol, 76:73-80, 2002.
2. Anis EA, O’Niell SH, Newkirk KM et al. Molecular characterization of the L1 gene of papillomaviruses in epithelial lesions of cats and comparative analysis with corresponding gene sequences of human and feline papillomaviruses. Am J Vet Res 71:1457-1461, 2010.
3. Aquino SM. Management of eyelid neoplasms in the dog and cat. Clin Tech Small Anim Pract 22:46-54, 2007.
4. Baradgì M, Fondevila D, Ferrer L. Immunohistochemical detection of COX-2 in feline and canine actinic keratoses and cutaneous squamous cell carcinoma. J Comp Path 146:11-17, 2012.
5. Beam SL, Rassnick KM, Moore AS et al. An immunohistochemical study of cyclooxygenase-2 expression in various feline neoplasms. Vet Pathol 40:496-500, 2003.
6. BexfieldNH, Stell AJ, Gear RN et al. Photodynamic therapy of superficial nasal planum squamous cell carcinomas in cats: 55 cases. J Vet Intern Med 22:1385-1389, 2009.
7. BostockDE. The prognosis in cats bearing squamous cell carcinoma. J Small Anim Pract, 13:119-125,1972
8. Buchholz J, Wergin M, Walt H et al., Photodynamic therapy of feline cutaneous squamous cell carcinoma using a newly developed liposomal photosensitizer: preliminary results concerning drug safety and efficacy. J Vet Intern Med 21:770-775, 2007.
9. Clarke RE. Cryosurgical treatment of feline cutaneous squamous cell carcinoma. Aust Vet Pract 21:148- ,1991.
10. De Vos J, Burm AGO, Focker BP. Results from the treatment of advanced stage squamous cell carcinoma of the nasal planum in cats, using a combination of intralesional carboplatin and superficial radiotherapy: a pilot study. Vet Compar Oncol 2:75-81, 2004.
11. Favrot C, Welle M, Heimann M et al. Clinical, histologic, and immunihistochemical analyses of feline squamous cell carcinoma in situ. Vet Pathol 46:25-33, 2009.
12. Fidel JL, Egger E, Blattmann H et al. Proton irradiation of feline nasal planum squamous cell carcinomas using an accelerated protocol Vet Radiol Ultrasound 42:569-575, 2001.
13. Gill VL, Bergman PJ, Baer KE et al. Use of imiquimod 5% cream (Aldara™) in cats with multicentric squamous cell carcinoma in situ: 12 cases (2002-2005). Vet Comp Oncol 6:55-64, 2008.
14. Goodfellow M, Hayes A, Murphy S et al. A retrospective study of ⁹⁰Strontium plesiotherapy for feline squamous cell carcinoma of the nasal planum. J Feline Med Surg 8:169-176, 2006.
15. Hammond GM, Gorodn IK, Théon AP et al., Evaluation of strontium Sr 90 for the treatment of superficial squamous cell carcinoma of the nasal planum in cats: 49 cases (1990-2006). J Am Vet Med Assoc 231:736-741, 2007.
16. Hunt G. Use of the lip-to-lid flap for replacement of the lower eyelid in five cats. Vet Surg 35:284-286, 2006.
17. Kitchell BK, Orenberg EK, Brown DM et al. Intralesional sustained-release chemotherapy with therapeutic implants for treatment of canine sun-induced squamous cell carcinoma. Eur J Cancer 31A:2093-2998, 1995.
18. Lana SE, Ogilvie GK, Withrow SJ et al. Feline cutaneous squamous cell carcinoma of the nasal planum and the pinnae:61 cases. J Am Anim Hosp Assoc 33:329-332, 1997.
19. Melzer K, Guscetti F, Rohrer Bley C et al. Ki67 reactivity in nasal and periocular squamous cell carcinomas in cats treated with electron beam radiation therapy. J Vet Intern Med 20:676-681, 2006.
20. Miller MA, Nelson SL, Turk JR et al. Cutaneous neoplasia in 340 cats. Vet Pathol 28:398-395, 1991.
21.  Moore AS, Ogilvie GK Skin tumors. In: Ogilvie GK, Moore AS, Feline oncology, Veterinary learning system, Trenton, NJ2001, 2001, pp. 398-428.
22. Munday JS, Kiupel M, French AF et al. Amplification of papillomaviral DNA sequences from a high proportion of feline cutaneous in situ and invasive squamous cell carcinomas using nested polymerase chain reaction. J Compil 19:259-263, 2008.
23. Nespeca G, Grest P, Rosenkrantz WS et al. Detection of novel papillomaviruslike sequences in paraffin-embedded specimens of invasive and in situ squamous cell carcinomas from cats. Am J Vet Res. 67:2036-2041, 2006.
24. O'Neill SH, Newkirk KM, Anis EA et al. Detection of human papillomavirus DNA in feline premalignant and invasive squamous cell carcinoma. Vet Dermatol 22:68-74, 2010.
25. Peters-Kennedy J, Scott DW, Miller Jr WH. Apparent clinical resolution of pinnal actinic keratoses and squamous cell carcinoma in a cat using topical imiquimod 5% cream. J Feline Med Surg 10:593-599, 2008.
26. Sabattini S, Marconato L, Zoff A et al. Epidermal growth factor receptor expression is predictive of poor prognosis in feline cutaneous squamous cell carcinoma.J Feline Med Surg,12:760-768, 2010.
27. Schmidt K, Bertani C, Martano M, et al. Reconstruction of the lower eyelid by third eyelid lateral advancement and local transposition cutaneous flap after “en bloc” resection of squamous cell carcinoma in 5 cats. Vet Surg, 34:78-82, 2005.
28. Sooriyaarachchi M, Narendran A, Gailer J. Comparative hydrolysis and plasma protein binding of cisplatin and carboplatin in human plasma in vitro. Metallomics. 3:49-55, 2011.
29. Spugnini EO, Vincenzi B, Citro G, et al. Electrochemotherapy for the treatment of squamous cell carcinoma in cats: a preliminary report. The Vet J 179:117-120, 2009.
30. Stell AJ, Dobson JM, Langmack K. Photodynamic therapy of feline superficial squamous cell carcinoma using topical 5-aminolaevulinc acid. J Small Anim Pract, 42:164-169, 2001.
31. Teifke JP, Lohr CV. Immunohistochemical detection of P53 overexpression in paraffin wax-embedded squamous cell carcinomas of cattle, horses, cats and dogs.J Comp Pathol, 4:205-210, 1996.
32. Théon AP, Madewell BR, Shearn VI et al. Prognostic factors associated with radiotherapy of squamous cell carcinoma of the nasal plane in cats. J Am Vet Med Assoc, 206:991-996, 1995.
33. Théon AP, VanVechten MK, Madewell BR. Intratumoral administration of carboplatin for treatment of squamous cell carcinomas of the nasal plane in cats. Am J Vet Res, 57:205-210, 1996.
34. Withrow SJ. Cancer of the nasal planum. In: Withrow SJ & Vail D, Small animal clinical oncology. 4° ed, W.B. Saunders, Philadelphia, 2007, pp. 511-515.
35. Withrow SJ, Straw RC. Resection of the nasal planum in nine cats and five dogs. J Am Anim Hosp Assoc 26:219-222, 1990.