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Compendium March 2009 (Vol 31, No 3)

Squamous Cell Carcinoma

by Julie Webb, DVM, DACVP, Rachel Burns, DVM, Holly Brown, DVM, Bruce LeRoy, DVM, PhD, DACVP, Carrie Kosarek, DVM, MS, DACVIM (Oncology)

    CETEST This course is approved for 3.0 CE credits

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    Abstract

    Squamous cell carcinoma (SCC) is a relatively common, malignant neoplasm of dogs and cats that can arise in a variety of locations. The gross appearance of SCC can be variable and nonspecific, so definitive diagnosis requires microscopic examination of the tissue (cytology or histology). Several treatment modalities exist, but surgical excision, if possible, is regarded as the best treatment option. Early diagnosis and treatment of SCC are key because small, early-stage tumors are the most amenable to treatment and carry the best prognosis.

    Squamous cell carcinoma (SCC) is a malignant neoplasm arising from squamous epithelium. The skin, oral cavity, and digits are the most common sites of SCC in dogs and cats.1 SCCs account for 15% of skin tumors in cats.2 Most cutaneous SCCs in cats occur on the head (FIGURE 1), often involving the pinna, eyelid, and nasal planum.2 In dogs, less than 5% of cutaneous neoplasms are SCC, and common sites include the legs, scrotum, perineum, nasal planum, and various lightly pigmented areas.1,3 SCCs account for 70% of feline and 25% of canine oral neoplasms and may arise from virtually any surface in the oral cavity, including the gingiva (FIGURE 2), tongue, tonsils, pharynx, lips, and buccal mucosa.1 In a retrospective series evaluating lingual lesions in dogs, more than one-half of the lesions were neoplastic, and 17% of those neoplasms were SCC.4 Of digital tumors in dogs (FIGURE 3), 38% to 50% are SCC, and multiple digits may be involved.5,6 Digital SCC was previously reported to be rare in cats, but a recent study diagnosed SCC in 24% of amputated feline digits.7 Other locations reported to develop SCC in dogs and cats include the conjunctiva, cornea, nasal passages, larynx, lung, esophagus, bladder, prostate, penis, cervix, vagina, and anal sac.1,8,9

    Most SCCs are locally invasive and, in certain areas of the body, exhibit bone invasion and osteolysis. Tumor spread to local lymph nodes may occur, but distant metastases are rare and usually do not occur until late in the disease process. However, certain anatomic locations have a higher rate of metastasis.  TABLE 1 lists some common sites of SCC and the biologic behavior associated with those sites.1

    A premalignant form of SCC, composed of dysplastic cells that do not cross the epithelial basement membrane, is called SCC in situ.10 Complete excision of an SCC in situ is curative for that lesion, but new lesions may develop in other areas. Two forms of SCC in situ have been reported in dogs and cats: solar keratosis and multicentric SCC in situ (MSCC). The lesions of solar keratosis are usually singular and range from an erythematous, scaly thickening of the skin to shallow, crusting lesions. They occur on lightly haired, nonpigmented skin and are associated with ultraviolet (UV) light exposure.3 With time and continued exposure to UV light, most solar keratosis lesions can progress to SCC. MSCC, similar to Bowen's disease in humans, presents as multiple plaque-like or papillary lesions on pigmented, haired skin and is not related to UV light exposure. MSCC is rare in cats and very rare in dogs.1,10 Its progression to SCC seems to be slow, if it occurs at all.

    Risk Factors and Etiology

    Older animals are at greater risk for developing SCC, with the average age at presentation being 8 to 10 years for dogs and 10 to 12 years for cats.2,3,10 Prolonged exposure to UV light, lack of skin pigment, and a sparse haircoat all contribute to the development of cutaneous SCC.1 Siamese cats, with their pigmented extremities, may be less likely to develop cutaneous SCC.2 Cats with long haircoats, such as Himalayans and Persians, also have a decreased risk, whereas domestic shorthaired cats are overrepresented.1 Dogs with white haircoats are more susceptible to cutaneous SCC, whereas dogs with dark haircoats appear to be overrepresented in cases of digital tumors.1,6 Rarely has a sex predilection been reported; in one study, female dogs appeared to be at increased risk for development of lingual SCC4, while tonsillar SCC may be more common in male dogs.11,12

    The mechanism frequently proposed for cutaneous SCC and its association with UV light involves the tumor suppressor gene p53.13 This gene encodes a protein (p53) that arrests the cell cycle when DNA damage is present, giving the cell time to repair the damage before continuing mitosis. If the damage cannot be repaired, p53 will induce apoptosis of the cell. UV light is a common carcinogen that can mutate the p53 gene. Cells in which the p53 gene is mutated continue replication even if DNA damage is present, leading to the accumulation of other mutations and a greater chance of neoplasia.13 The mutant form of p53 has been detected in 82% of feline pinna SCCs, emphasizing the importance of p53 in preventing solar-induced SCC.13

    Few studies investigating carcinogens that may contribute to the development of SCC in cats and dogs have been conducted. Reported risk factors for oral SCC in cats include wearing flea collars and eating canned food (especially tuna-based food).14 Small but statistically insignificant correlations have been found between environmental tobacco smoke and feline oral SCC.14,15 Urban pollutants may increase the risk for tonsillar SCC.3

    Another potential contributor to the development of SCC in dogs and cats is chronic inflammation. Chronic dermatosis is a reported risk factor for cutaneous SCC,16 and, although extremely rare, bilateral aural SCC was reported in two dogs that had a history of chronic aural inflammation.17 In addition, multiple corneal SCCs developed in a dog with keratoconjunctivitis sicca.18

    Viral etiologies have been linked to certain SCCs in people. Papillomavirus type 16 infection is associated with a significant number of SCCs of the head and neck in humans, particularly in the oropharynx and in patients lacking the risk factors of tobacco and alcohol consumption.19 Papillomavirus DNA has been detected within approximately 20% of canine and feline cutaneous and mucosal SCCs, but the significance of this association has yet to be determined.20,21

    Radiation-induced carcinogenesis is well documented in people and animals, as reviewed by Suit and colleagues in 2007.22 In one study23 evaluating orthovoltage radiotherapy for the treatment of acanthomatous epulides (now called acanthomatous ameloblastomas), seven of 39 dogs (18%) developed second tumors within the radiation field; 71% of the tumors were SCC. However, a more recent study24 found that the risk of developing a second tumor was less than 4%. In this study, only two of 57 dogs that underwent definitive radiation therapy (RT) for acanthomatous epulides developed second tumors, both of which were sarcomas. The authors of the more recent study suggest that the earlier paper may have included patients whose original tumors were SCC, misdiagnosed as acanthomatous epulides.

    Gross Description and Clinical Signs

    In many cases of SCC, the animal presents with a visible mass. The mass may appear as any of the following3:

    • Shallow crusting lesion (often SCC in situ)
    • Deeply ulcerated lesion
    • Proliferative, raised, red plaque
    • Cauliflower-shaped growth

    The appearance of the lesion may change over time, often progressing from a shallow or ulcerated lesion to a more proliferative, raised tumor. The time from lesion occurrence to diagnosis also varies but is generally prolonged. In two studies of cats with SCC of the nasal planum or pinnae, lesions were reportedly present for a median duration of 3 to 5 months before diagnosis.25,26 Often, the tumor is initially misdiagnosed as an inflammatory or traumatic lesion, and therapies such as antibiotics and corticosteroids may have been used before diagnosis.25

    Clinical signs of SCC depend on the tumor's location. Digital tumors often cause lameness and ulceration of the digit.5 Nasal tumors can cause facial deformity, nasal discharge, and sneezing. Signs of oral tumors include excess salivation, oral bleeding, anorexia, loose teeth, dysphagia, weight loss, and halitosis.27 Numerous other clinical signs have been reported: coughing and dyspnea with pulmonary tumors, regurgitation with esophageal masses, voice change with laryngeal SCC, and ocular discharge with periocular and ocular tumors.1 Hypertrophic osteopathy is a rare complication with pulmonary SCC.28

    There are no consistent abnormal laboratory findings in animals with SCC. One study found that 32% of cats with oral SCC had a neutrophilic leukocytosis, likely reflecting secondary infection of ulcerated masses.27 One case of paraneoplastic neutrophilic leukocytosis has been reported with pulmonary SCC,29 and several cases of paraneoplastic hypercalcemia have been documented.30

    Diagnosis

    Early diagnosis of SCC is paramount for early therapeutic intervention, which may result in long-term control or cure for affected patients. SCC may be suspected based on the gross appearance of a lesion and its location, but definitive diagnosis requires microscopic examination of the affected tissue. Cytology is a rapid, easy, noninvasive method that may provide the diagnosis of SCC and is often attempted as the first diagnostic technique, especially for cutaneous lesions. Biopsy with histopathology may be required to obtain a definitive diagnosis if cytology is nondiagnostic or equivocal.

    Cytology

    Several methods may be used to obtain a specimen for cytologic analysis. The best method depends on the lesion location and gross appearance. Fine-needle aspiration is used to obtain material from nodular lesions, whereas surface imprints and scrapings are often used to collect material from shallow or plaquelike lesions. Unfortunately, many SCCs are ulcerated and inflamed, so superficial sampling may retrieve only the inflammation and not the deeper neoplastic cells. Impression smears from biopsy samples also provide material for cytologic examination.

    As with other epithelial neoplasms, SCCs tend to exfoliate readily, leading to highly cellular samples. The cells may be in closely adherent sheets or clusters, although numerous individual cells are often present. Squamous cells undergo several stages of maturation; thus, a pleomorphic population of cells may be observed. Immature (basal-type) squamous cells are small, round to cuboidal cells with a scant amount of glassy, basophilic cytoplasm and a high nuclear-cytoplasmic ratio. Mature (superficial) squamous cells are large, angular cells with a large amount of lightly basophilic cytoplasm and pyknotic or absent nuclei.31 Keratinized cells have deeply basophilic cytoplasm with angular borders. Poorly differentiated SCCs consist predominantly of immature cells, and well-differentiated tumors contain more mature cells.

    Asynchronous nuclear and cytoplasmic maturation, in which large, fully keratinized cells retain large nuclei, is commonly seen with SCC (FIGURE 4). Other criteria of malignancy found in SCC include prominent anisocytosis and anisokaryosis, multinucleated cells, and variable numbers and sizes of nucleoli. Keratohyaline granules are frequently present as small, round, cytoplasmic vacuoles concentrated around the nucleus. SCC cells may also display emperipolesis, in which other cells are able to passively penetrate the neoplastic squamous cell and are found within its cytoplasm31 (FIGURE 5). Cells with a long cytoplasmic process resembling a tail, called tadpole cells, are occasionally observed (FIGURE 6).

    The cytologic diagnosis of SCC is often complicated by concurrent inflammation. Secondary inflammation, often present when the tumor is ulcerated, may mask the neoplastic cell population. Additionally, primary inflammatory conditions can induce epithelial hyperplasia, creating dysplastic changes, such as increased cytoplasmic basophilia, anisocytosis, and anisokaryosis, that mimic neoplasia (FIGURE 7). Therefore, extreme caution should be used when attempting to diagnose SCC on cytology in a highly inflamed area. Histologic examination of the lesion may be necessary for a definitive diagnosis in these situations.

    Other samples containing squamous cells, such as contaminated slides, papillomas, and keratin-producing cysts or tumors (FIGURE 8), must be differentiated from SCC on cytology.  TABLE 2 details features that can help distinguish these lesions from SCC.31

    Histology

    Biopsy of the lesion and histologic analysis are often needed to definitively diagnose SCC, especially if the tumor is poorly differentiated or highly inflamed. If not excisional, the biopsy should always contain the junction of grossly normal and abnormal epithelium, as this is usually the most diagnostic region. A typical well-differentiated SCC maintains a loose epithelial maturation sequence from basal layer to stratum corneum, but instead of growing toward the skin surface, the neoplastic cells form irregular whorls and cords within the tumor (FIGURE 9). Nests of neoplastic cells surrounded by stroma may have the equivalent of the basal cell layer at the outer edge of the nest and the keratin-producing layer in the center, creating the classic appearance of intensely eosinophilic, densely packed rings of keratin (a keratin pearlFIGURE 10). In less differentiated tumors, epithelial layering is indistinct, cells are smaller, and keratinization is less likely to be seen. Highly anaplastic SCCs may require special immunohistochemical stains, such as cytokeratin, to positively identify the cell of origin.1

    Staging

    SCC is typically a locally aggressive neoplasm with a variable potential for distant metastasis. Diagnostic staging tests that may be advised include routine hematologic and biochemical analysis, urinalysis, local lymph node evaluation, three-view thoracic radiography, and abdominal imaging (radiography and ultrasonography). The extent of staging that is undertaken is often dictated by the primary tumor location. Advanced imaging techniques, such as computed tomography, may be required to further define the location and extent of the primary tumor, especially for tumors involving the ear canal, oral, and sinonasal cavities.32-34 Imaging is also useful for surgical and radiation treatment planning.

    Treatment Options and Prognosis

    Early diagnosis and implementation of therapy is advised for all patients with SCC, especially because small tumors are more amenable to local control. Local treatment options for dogs and cats with SCC include surgery, cryotherapy, RT, plesiotherapy, photodynamic therapy (PDT), and intratumoral chemotherapy. Systemic therapy, such as chemotherapy and cyclooxygenase-2 (COX-2) inhibitors, may be advised for patients with SCCs that are inoperable, are poorly differentiated, have metastasized at the time of diagnosis, or are in a location with a reportedly aggressive biologic behavior (TABLE 1). It is important to note that, with certain forms of SCC (i.e., those induced by UV light), cellular damage may already be present at other sites. Therefore, new lesions may develop even with excellent local control of the primary lesion.

    Surgical Excision

    Surgical excision is the primary treatment option for most patients with SCC. The ability to completely excise the tumor depends on factors such as the size and location of the tumor. In a retrospective study25 evaluating response to therapy (surgery, RT, or cryotherapy) in 61 cats with nasal planum or pinna SCC, surgery provided the longest disease-free interval, with a median of 594 days. Early surgical intervention is also advised for digital tumors. Digital amputation resulted in complete tumor control for all but one of 21 dogs with subungual SCC.35 If complete surgical excision is not possible, adjuvant therapies may be pursued.

    Cryotherapy

    Cryotherapy may be considered for local control of small, superficial tumors or tumors that are incompletely excised. It is inexpensive and readily available and provides excellent cosmetic results. Studies have reported that cryotherapy provides good local control for 1 year or longer for SCCs of the cornea.18,36 For the pinna and nasal planum, cryotherapy provided a median disease-free interval of 254 days in 11 cats.25 In a larger study37 of cats with nasal planum SCC treated with cryotherapy, the median remission time was 26.7 months.

    Radiation Therapy

    Definitive RT is a local treatment modality that is generally recommended as an adjuvant treatment for incompletely excised tumors or as a primary treatment for inoperable tumors. In the case of SCC, RT is most commonly employed for tumors of the nasal planum, nasal cavity, and oral cavity. The response to definitive RT for dogs with oral SCC varies with the size of the tumor: small, early-stage tumors had the best response and the longest progression-free intervals38 (FIGURE 11). In cats with nasal planum SCC treated with definitive RT, the 1- and 5-year survival rates were 60% and 10%, respectively.39 In dogs, nasal planum tumors treated with RT recurred in an average of 2 to 3 months, and the median survival time was 6 months.40,41 The median survival time of eight dogs with tonsillar SCC treated with surgery plus definitive RT was 110 days.11 Protocols vary among institutions; however, most protocols involve low-dose fractions (3 to 4 Gy) given daily to every other day over a 3- to 4-week period. The side effects of these protocols are generally mild and limited to acute reactions such as mucosal inflammation. No radiation-induced tumors have been specifically reported with these protocols, but any RT has the potential to induce neoplasia.

    Palliative RT typically involves a total of three to four treatments given at a higher dose per fraction than definitive RT. The goals of palliative RT are to provide pain relief, stabilize tumor growth, or improve dysfunction associated with the tumor. Palliative RT may be recommended for patients for which a cure is not possible due to advanced local or metastatic disease or other severe illness. Unfortunately, reports evaluating the efficacy of palliative RT in dogs and cats with SCC are limited, and the few that exist are not encouraging. A 2001 study evaluating palliative RT in seven cats with nonresectable oral SCC found that 87% of the cats had tumor progression or acute radiation side effects, with a mean survival time of only 60 days.42

    Plesiotherapy

    Plesiotherapy involves the topical application of a radiation source to the target lesion. Topical radiation doses drop off significantly after a depth of 2 mm; therefore, the use of plesiotherapy is limited to superficial or incompletely excised tumors, particularly those of the nasal planum or ocular region. In a recent retrospective study26 evaluating the efficacy of strontium-90 plesiotherapy for cats with nasal planum SCC, 13 of 15 cats achieved a complete response with a median disease-free interval of 692 days. Excellent cosmetic results were also obtained. Strontium-90 plesiotherapy has also been used to treat SCC in dogs.43

    Photodynamic Therapy

    PDT is yet another local treatment modality that has been used for treatment of SCC. The process involves the topical administration or intravenous injection of a photosensitizer that preferentially accumulates in neoplastic cells. Once activated by light of a specific wavelength, the photosensitizer causes cytotoxicity and tissue necrosis. Studies of intravenous PDT44,45 in dogs and cats with oral and cutaneous SCC have shown moderate to good response rates (62% to 73% of patients experience a cure or good local control) that last 1 year or longer. In a more recent study46 evaluating topical PDT in cats with facial SCC, 85% achieved a complete response. Unfortunately, 63% of these cats developed recurrence in a median time of 21 weeks. The results of these studies suggest that PDT may be an effective local treatment modality, but PDT is not readily available in private practice.

    Chemotherapy

    SCCs generally are not considered chemoresponsive tumors; however, chemotherapy may be considered under certain circumstances. For example, chemotherapy may be advised for tumors that are inoperable, anaplastic, or metastatic at the time of diagnosis. Single-agent or combination therapy protocols containing bleomycin, cisplatin, carboplatin, cyclophosphamide, doxorubicin, and 5-fluorouracil have been evaluated.12,47 In 16 dogs with tonsillar SCC treated with multidrug chemotherapy, there was no appreciable reduction in tumor volume, and 62% of the dogs were euthanized because of progressive disease.12

    There are few reports of the use of intratumoral chemotherapy for cats and dogs with SCC.48-50 Intratumoral therapy with a cisplatin analog was ineffective in cats with oral SCC, many of which experienced signs of toxicity ranging from lethargy and inappetence to acute anaphylactoid reactions.49 In comparison, intratumoral treatment with carboplatin appeared safe and effective for cats with nasal planum SCC.48 In a study of 13 dogs with cutaneous SCC treated with intratumoral sustained-release chemotherapy (5-fluorouracil or cisplatin), all the dogs had a 50% or greater response, and 54% achieved a complete response.50 The mean disease-free interval was 153 weeks. The use of chemotherapeutics as sensitizers before RT has also been evaluated in dogs and cats with SCC. Cisplatin combined with RT has shown some promise in dogs with nasal SCC,51 while results of combining gemcitabine with RT are less encouraging.52,53

    COX-2 Inhibitors

    COX-2 is an inducible enzyme responsible for the production of inflammatory prostaglandins. Overexpression of COX-2 has been implicated in the progression of certain cancers, specifically carcinomas. Several studies in dogs and cats have reported increased expression of COX-2 in SCCs in various locations.54-58 In light of these findings, the role of COX-2 inhibitors in the management of SCC needs to be further explored.

    In addition to their antiinflammatory effects, COX-2 inhibitors may have antitumor properties. The use of piroxicam, a nonspecific COX inhibitor, given alone or in combination with other therapies has been evaluated in dogs with SCC.59-62 Schmidt and colleagues60 prospectively evaluated the efficacy of daily oral piroxicam in 17 dogs with measurable oral SCC. Three dogs obtained partial or complete remission for a median of 180 days; five other dogs had stable disease for a median of 102 days. A recent pharmacokinetic study evaluating piroxicam in cats with carcinoma suggested that a dose of 0.3 mg/kg/day PO would be appropriate for clinical trial use in cats with COX-2-positive oral SCC.58 Although these studies have shown only minimal toxicity (mild vomiting or diarrhea in a few animals), it should be noted that, as a nonspecific COX inhibitor, piroxicam can induce serious side effects, including gastrointestinal ulceration and renal failure. COX-2-selective inhibitors have a lower incidence of these side effects, but, as yet, there are no studies evaluating their effect on SCC.

    Novel and Multimodality Therapies

    Immunotherapy, the stimulation of the immune system to "reject" a tumor, has been employed in human medicine for treating a variety of cancers, including SCC. Experience with this therapy in small animal medicine is limited. Imiquimod is a topical immunomodulator that induces cytokine production and may induce tumor apoptosis.63 In a small retrospective study64 evaluating the efficacy and toxicity of topical imiquimod in cats with MSCC, treatment appeared effective in all 12 cats and was associated with mild toxicity (local erythema in three cats, partial anorexia in one cat, and increased liver enzymes and neutropenia in one cat).

    Retinoids (vitamin A derivatives) have been evaluated for the treatment of solar-induced SCC and its associated preneoplastic lesions (solar keratosis). In a study assessing the efficacy of etretinate for dogs with solar-induced preneoplastic lesions, five of 10 dogs showed a partial or complete response.65 However, therapeutic efficacy of 13-cis-retinoic acid was not evident in 10 cats with preneoplastic lesions or SCC of the head.66

    A multimodal approach to treating dogs and cats with SCC may provide the most therapeutic benefit when surgery cannot be curative. The efficacy of a combination of surgery, carboplatin, and RT was reported in five dogs with tonsillar SCC: the mean survival time was 211 days.67 In an earlier study, five of six dogs with tonsillar SCC treated with a combination of surgery, doxorubicin, cisplatin, and RT had a complete response with a median disease-free interval of 240 days.12 Carboplatin combined with RT has also been employed for treatment of nasal planum SCC in cats with a good response (six of six cats had a complete response and no recurrence for up to 268 days).68 Further prospective studies evaluating multimodal therapy are warranted.

    Conclusion

    SCCs are common tumors of dogs and cats. They vary in appearance, location, and biologic behavior; however, they are typically locally aggressive, with a reported low to moderate metastatic potential. Early recognition, diagnosis, and treatment are essential. Diagnosis of SCC relies on cytologic or histologic examination of the tumor. Many treatment modalities are available, with surgical excision being the mainstay of therapy. The prognosis for patients with SCC varies. A favorable prognosis exists for patients with well-differentiated tumors that can be completely excised and without evidence of vascular or lymphatic invasion or distant metastases. Conversely, the prognosis is poor for patients with inoperable or poorly differentiated tumors or with metastatic disease. Further investigation into the tumorigenesis of SCC is warranted. The findings of these studies may lead to additional preventive measures and novel treatment modalities that improve outcomes for dogs and cats with this type of cancer.

    Acknowledgment

    The authors thank Dr. C. G. Couto for his editing assistance.

    Downloadable PDF

    Dr. LeRoy discloses that he has received financial support from Novartis Animal Health and Pfizer Animal Health.

    1. Meuten DJ. Tumors in Domestic Animals. 4th ed. Ames: Blackwell Publishing; 2002.

    2. Miller MA, Nelson SL, Turk JR, et al. Cutaneous neoplasia in 340 cats. Vet Pathol 1991;28(5):389-395.

    3. Withrow SJ, Vail DM. Withrow and MacEwen's Small Animal Clinical Oncology. 4th ed. Philadelphia: WB Saunders; 2006.

    4. Dennis MM, Ehrhart N, Duncan CG, et al. Frequency of and risk factors associated with lingual lesions in dogs: 1,196 cases (1995-2004). JAVMA 2006;228(10):1533-1537.

    5. Marino DJ, Matthiesen DT, Stefanacci JD, et al. Evaluation of dogs with digit masses: 117 cases (1981-1991). JAVMA 1995;207(6):726-728.

    6. Henry CJ, Brewer WG Jr, Whitley EM, et al. Canine digital tumors: a veterinary cooperative oncology group retrospective study of 64 dogs. J Vet Intern Med 2005;19(5):720-724.

    7. Wobeser BK, Kidney BA, Powers BE, et al. Diagnoses and clinical outcomes associated with surgically amputated feline digits submitted to multiple veterinary diagnostic laboratories. Vet Pathol 2007;44:362-365.

    8. Leib MS, Saunders GK, Dallman MJ, Carrig CB. Squamous cell carcinoma of the prostate gland in a dog. JAAHA 1986;22:509-514.

    9. Esplin DG, Wilson RS, Hullinger GA. Squamous cell carcinoma of the anal sac in five dogs. Vet Pathol 2003;40:332-334.

    10. Baer KE, Helton K. Multicentric squamous cell carcinoma in situ resembling Bowen's disease in cats. Vet Pathol 1993;30(6):535-543.

    11. MacMillan R, Withrow SJ, Gillette EL. Surgery and regional irradiation for treatment of canine tonsillar squamous cell carcinoma: retrospective review of eight cases. JAAHA 1982;18:311-314.

    12. Brooks MB, Matus RE, Leifer CE, et al. Chemotherapy versus chemotherapy plus radiotherapy in the treatment of tonsillar squamous cell carcinoma in the dog. J Vet Intern Med 1988;2:206-211.

    13. 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 1996;114:205-210.

    14. Bertone ER, Snyder LA, Moore AS. Environmental and lifestyle risk factors for oral squamous cell carcinoma in domestic cats. J Vet Intern Med 2003;17(4):557-562.

    15. Snyder LA, Bertone ER, Jakowski RM, et al. p53 expression and environmental tobacco smoke exposure in feline oral squamous cell carcinoma. Vet Pathol 2004;41:209-214.

    16. Hargis AM, Thomassen RW, Phemister RD. Chronic dermatosis and cutaneous squamous cell carcinoma in the beagle dog. Vet Pathol 1977;14:218-228.

    17. Zur G. Bilateral ear canal neoplasia in three dogs. Vet Dermatol 2005;16(4):276-280.

    18. Ward DA, Latimer KS, Askren RM. Squamous cell carcinoma of the corneoscleral limbus in a dog. JAVMA 1987;190(11):1430-1432.

    19. Li G, Sturgis EM. The role of human papillomavirus in squamous cell carcinoma of the head and neck. Curr Oncol Rep 2006;8(2):130-139.

    20. Zaugg N, Nespeca G, Hauser B, et al. Detection of novel papillomaviruses in canine mucosal, cutaneous and in situ squamous cell carcinomas. Vet Dermatol 2005;16(5):290-298.

    21. 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 2006;67(12):2036-2041.

    22. Suit H, Goldberg S, Niemierko A, et al. Secondary carcinogenesis in patients treated with radiation: a review of data on radiation-induced cancers in humans, non-human primate, canine and rodent subjects. Radiat Res 2007;167:12-42.

    23. Thrall DE. Orthovoltage radiotherapy of acanthomatous epulides in 39 dogs. JAVMA 1984;184(7):826-829.

    24. McEntee MC, Page RL, Theon A, et al. Malignant tumor formation in dogs previously irradiated for acanthomatous epulis. Vet Radiol Ultrasound 2004;45(4):357-361.

    25. Lana SE, Ogilvie GK, Withrow SJ, et al. Feline cutaneous squamous cell carcinoma of the nasal planum and the pinnae: 61 cases. JAAHA 1997;33(4):329-332.

    26. Goodfellow M, Hayes A, Murphy S, et al. A retrospective study of (90)Strontium plesiotherapy for feline squamous cell carcinoma of the nasal planum. J Feline Med Surg 2006;8(3):169-176.

    27. Postorino Reeves NC, Turrel JM, Withrow SJ. Oral squamous cell carcinoma in the cat. JAAHA 1993;25(9):438-441.

    28. Brodey RS. Hyerptrophic osteoarthropathy in the dog: a clinicopathologic survey of 60 cases. JAVMA 1971;159(10):1242-1256.

    29. Dole RS, MacPhail CM, Lappin MR. Paraneoplastic leukocytosis with mature neutrophilia in a cat with pulmonary squamous cell carcinoma. J Feline Med Surg 2004;6(6):391-395.

    30. Klausner JS, Bell FW, Hayden DW, et al. Hypercalcemia in two cats with squamous cell carcinomas. JAVMA 1990;196(1):103-105.

    31. Raskin RE, Meyer DJ. Atlas of Canine and Feline Cytology. Philadelphia: WB Saunders; 2001.

    32. Saunders JH, Van Bree H, Gielen I, et al. Diagnostic value of computed tomography in dogs with chronic nasal disease. Vet Radiol Ultrasound 2003;44(4):409-413.

    33. Schoenborn WC, Wisner ER, Kass PP, et al. Retrospective assessment of computed tomographic imaging of feline sinonasal disease in 26 cats. Vet Radiol Ultrasound 2003;44(2):185-195.

    34. Tromblee TC, Jones JC, Etue AE, et al. Association between clinical characteristics, computed tomography characteristics, and histologic diagnosis for cats with sinonasal disease. Vet Radiol Ultrasound 2006;47(3):241-248.

    35. O'Brien MG, Berg J, Engler SJ. Treatment by digital amputation of subungual squamous cell carcinoma in dogs: 21 cases (1987"1988). JAVMA 1992;201(5):759-761.

    36. Latimer KS, Kaswan RL, Sundberg JP. Squamous cell carcinoma of the corneoscleral limbus in a dog. JAVMA 1987;190(11):1430-1432.

    37. Clarke RE. Cryosurgical treatment of feline cutaneous squamous cell carcinoma. Aust Vet Pract 1991;21(3):148-153.

    38. Theon AP, Rodriguez C, Madewell BR. Analysis of prognostic factors and patterns of failure in dogs with malignant oral tumors treated with megavoltage irradiation. JAVMA 1997;210(6):778-784.

    39. Theon AP, Madewell BR, Shearn VI, et al. Prognostic factors associated with radiotherapy of squamous cell carcinoma of the nasal plane in cats. JAVMA 1995;206(7):991-996.

    40. Thrall DE, Adams WM. Radiotherapy of squamous cell carcinomas of the canine nasal plane. Vet Radiol Ultrasound 1982;23(5):193-195.

    41. Lascelles BD, Parry AT, Stidworthy MF, et al. Squamous cell carcinoma of the nasal planum in 17 dogs. Vet Rec 2000;147:473-476.

    42. Bregazzi VS, LaRue SM, Powers BE, et al. Response of feline oral squamous cell carcinoma to palliative radiation therapy. Vet Radiol Ultrasound 2001;42(1):77-79.

    43. Andrade AL, Fernandes MAR, Biazzona L, et al. Clinical trial with strontium-90 low radiation for treatment of third eyelid neoplasms in dogs. Proc Genes Dogs Cancer 3rd Annu Canine Cancer Conf 2003.

    44. McCaw DL, Pope ER, Payne JT, et al. Treatment of canine oral squamous cell carcinoma with photodynamic therapy. Br J Cancer 2000;82(7):1297-1299.

    45. Chang CJ, Lai YL, Wong CJ. Photodynamic therapy for facial squamous cell carcinoma in cats using Photofrin. Changgeng Yi Xue Za Zhi 1998;21(1):13-19.

    46. Stell AJ, Dobson JM, Langmack K. Photodynamic therapy of feline superficial squamous cell carcinoma using topical 5-aminolaevulinic acid. J Small Anim Pract 2001;42(4):164-169.

    47. Buhles WC, Theilen GH. Preliminary evaluation of bleomycin in feline and canine squamous cell carcinoma. Am J Vet Res 1973;34(2):289-291.

    48. Theon 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 1996;57(2):205-210.

    49. Fox LE, Rosenthal RC, King RR, et al. Use of cis-bis-neodecanoato-trans-R,R-1, 2-diaminocyclohexane platinum (II), a liposomal cisplatin analogue, in cats with oral squamous cell carcinoma. Am J Vet Res 2000;61(7):791-795.

    50. 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 195;31A(12):2093-2098.

    51. Lana SE, Dernell WS, Lafferty MH, et al. Use of radiation and a slow-release cisplatin formulation for treatment of canine nasal tumors. Vet Radiol Ultrasound 2004;45(6):577-581.

    52. Jones PD, de Lorimier LP, Kitchel BE, et al. Gemcitabine as a radiosensitizer for nonresectable feline oral squamous cell carcinoma. JAAHA 2003;39:463-467.

    53. LeBlanc AK, LaDue TA, Turrel JM, et al. Unexpected toxicity following use of gemcitabine as a radiosensitizer in head and neck carcinomas: a veterinary radiation therapy oncology group pilot study. Vet Radiol Ultrasound 2005;45(5):466-470.

    54. De Almeida EMP, Piche C, Sirois J, et al. Expression of cyclo-oxygenase-2 in naturally occurring squamous cell carcinomas in dogs. J Histochem Cytochem 2001;49:867-876.

    55. Beam SL, Rassnick KM, Moore AS, et al. An immunohistochemical study of cyclooxygenase-2 expression in various feline neoplasms. Vet Pathol 2003;40:496-500.

    56. Mohammed SI, Khan KN, Sellers RS, et al. Expression of cyclooxygenase-1 and 2 in naturally-occurring canine cancer. Prostaglandins Leukot Essent Fatty Acids 2004;70(5):479-483.

    57. Hayes A, Scase T, Miller J, et al. COX-1 and COX-2 expression in feline oral squamous cell carcinoma. J Comp Pathol 2006;135(2-3):93-99.

    58. DiBernardi L, Dore M, Davis JA, et al. Study of feline oral squamous cell carcinoma: potential target for cyclooxygenase inhibitor treatment. Prostaglandins Leukot Essent Fatty Acids 2007;76:245-250.

    59. Knapp DW, Richardson RC, Bottoms GD, et al. Phase I trial of piroxicam in 62 dogs bearing naturally occurring tumors. Cancer Chemother Pharmacol 1992;29(3):214-218.

    60. Schmidt BR, Glickman NW, DeNicola DB, et al. Evaluation of piroxicam for the treatment of oral squamous cell carcinoma in dogs. JAVMA 2001;218(11):1783-1786.

    61. Boria PA, Murray DJ, Bennett PF, et al. Evaluation of cisplatin combined with piroxicam for the treatment of oral malignant melanoma and oral squamous cell carcinoma in dogs. JAVMA 2004;224(3):388-394.

    62. Langova V, Mutsaers AJ, Phillips B, et al. Treatment of eight dogs with nasal tumors with alternating doses of doxorubicin and carboplatin in conjunction with oral piroxicam. Aust Vet J 2004;82(11):676-680.

    63. Shon M, Schon MP. The antitumoral mode of action of imiquimod and other imidazoquinolones. Curr Med Chem 2007;14(6):681-687.

    64. Gill V, Bergman P, Baer K, et al. Evaluation of imiquimod 5% (Aldara) in cats with multicentric squamous cell carcinoma in situ (MSCCIS). Proc 26th Vet Cancer Soc 2006:18.

    65. Marks SL, Song MD, Stannard AA, et al. Clinical evaluation of etretinate for the treatment of canine solar-induced squamous cell carcinoma and preneoplastic lesions. J Am Acad Dermatol 1992;27(1):11-16.

    66. Evans AG, Madewell BR, Stannard AL. A trial of 13-cis-retinoic acid for the treatment of squamous cell carcinoma and preneoplastic lesions of the head in cats. Am J Vet Res 1985;46(12):2553-2557.

    67. Murphy S, Hayes A, Adams V, et al. Role of carboplatin in multi-modality treatment of canine tonsillar squamous cell carcinoma—a case series of five dogs. J Small Anim Pract 2006;47(4):216-220.

    68. De Vos JP, 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 Comp Oncol 2004;2(2):75-81.

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