In four studies comprising 81 cats with oral squamous cell carcinoma, 12 cats (14.8%) had documented metastasis to the ipsilateral submandibular lymph node.3-6 The actual rate of metastasis may have been somewhat higher, as not all cases had cytologic or histologic lymph node evaluation. In eight cats (10%), metastasis was diagnosed at presentation,3-5 while four cats (5%) developed lymph node metastasis after primary tumor treatment.6 Of these four cats, one was euthanized because of the metastasis; the other three were euthanized because of local tumor progression.6 Thoracic radiographs were evaluated in three of the studies, comprising 74 cats, and no evidence of thoracic metastasis was present at initial presentation in any patient.3,5,6 In one cat that had lymph node metastasis, follow-up thoracic radiographs 16 months after treatment showed no evidence of pulmonary metastatic spread.4 These findings are consistent with the belief that feline maxillofacial squamous cell carcinomas have a low metastatic rate and that local disease is usually the cause of death.
ETIOLOGY AND RISK FACTORS
The average age of cats with oral squamous cell carcinoma is 12.5 years, with a range of 3 to 21 years. No significant sex or breed predilection is associated with this tumor. Although several environmental risk factors have been recognized, the cause of feline oral squamous cell carcinoma remains poorly defined. Various potential contributing factors are discussed below.
One clinical study found that cats exposed to household environmental tobacco smoke appear to have an increased risk of developing oral squamous cell carcinoma.7 Cats that had ever lived in a household with a smoker had a nonstatistically significant twofold increase in risk of oral squamous cell carcinoma compared with cats in nonsmoking households. Cats whose owners reported smoking one to 19 cigarettes a day had a statistically significant fourfold increase in the risk of oral squamous cell carcinoma compared with cats in nonsmoking households.7
Another study of p53 expression in oral squamous cell carcinoma determined that cats exposed to any environmental tobacco smoke were four and a half times more likely to overexpress p53 in their tumors than were unexposed cats.8 The p53 protein, the product of a tumor suppressor gene, regulates cell growth and proliferation and prevents unrestrained cell division after chromosomal damage. Abnormal p53 accumulates in the cell, unlike normal, wild-type p53, and can be detected via immunohistochemistry. The absence of functional p53 increases the risk of developing various cancers, and it is suggested that p53 may be a possible site for carcinogen-related mutations within some squamous cell carcinomas.8
Flea control collars
In one study, cats that wore flea collars had a statistically significant fivefold increased risk of developing oral squamous cell carcinoma when compared with control cats.7 This increased risk was possibly due to the proximity of the collar pesticides to the oral cavity.7 The use of flea shampoos, however, was associated with a 90% reduction in the risk of developing oral squamous cell carcinoma. This finding may be associated with regular shampooing causing a decrease of chemical contaminants on the coat and, thus, decreased oral intake of chemicals by the cats through grooming.7
The same study that evaluated passive smoke exposure also revealed a statistically significant threefold increase in oral squamous cell carcinoma in cats that frequently ate canned cat food when compared with those eating dry food.7 Additionally, cats that ate canned tuna had a statistically significant five-time higher risk for oral squamous cell carcinoma tumor development when compared with cats that did not consume canned tuna.7 The increase could be related to differences in the nutrient content of these foods. Another explanation for the difference in risk among food types may be that cats eating dry food have less tartar buildup and, thus, better oral hygiene than those that eat canned food.4
DIAGNOSIS AND STAGING
History and physical examination
A one-year prospective study in which 24 cats presented for evaluation of mandibular swellings revealed that 12 of the cats had malignant tumors while the other 12 cats had benign lesions.9 The malignant tumors included eight squamous cell carcinomas, two lymphomas, one melanoma, and one adenocarcinoma.9 Almost all the nonmalignant swellings in this study were caused by osteomyelitis secondary to dental disease, such as end-stage odontoclastic resorptive lesions, severe periodontal disease, and endodontic disease secondary to chronic pulpal exposure associated with canine tooth fractures. Clinical and radiographic findings could not differentiate benign from malignant mandibular lesions.9 Thus, a biopsy is crucial for obtaining an accurate diagnosis.
Laboratory tests to identify concurrent disease
Imaging to determine the extent of invasion
Computed tomography is a more sensitive way to define the extent of the tumor before surgery or radiation therapy. Ultrasonography may also be used to help delineate the soft tissue margins of lingual squamous cell carcinoma.14
Fine-needle aspiration to assess the primary lesion and regional lymph nodes
The primary lesion may be aspirated to provide a rapid preliminary assessment via cytologic examination. If sedation is required to obtain the aspirate, be prepared to also do an incisional biopsy (see below).
While rare, the most common sites of metastasis for oral squamous cell carcinoma in cats are the mandibular or retropharyngeal lymph nodes. Regional lymph nodes, whether enlarged or not, need to be assessed via fine-needle aspiration and cytologic examination. Physical examination alone is a poor indicator of lymph node metastasis. In a study of seven cats and 37 dogs with a variety of solid tumors, six out of 27 (22%) animals in which lymph nodes were normal-sized or only slightly enlarged had metastatic disease identified via cytology.15 The sensitivity of cytologic evaluation of fine-needle aspirates was 100% (no false negative results), and the specificity was 96% (13 of 14 that had cytologic evidence of metastasis to regional lymph nodes also had histologic evidence), signifying that fine-needle aspiration is a consistent method of assessing the regional lymph nodes.15
Just as normal-sized nodes may contain tumor cells, enlarged nodes may not. In a study of seven cats treated with mandibulectomy and ipsilateral lymph node excision, two nodes noted to be large and firm on physical examination were histologically free of tumor cells, while one nonpalpable node had metastasis.4 In another study of 52 cats with oral squamous cell carcinoma, 15 (29%) cats had enlarged regional lymph nodes, but only seven (13%) of the cats had evidence of squamous cell carcinoma in the node on cytologic examination of a fine-needle aspirate.5 These findings provide further support that physical examination alone is insufficient to determine lymph node status in these patients and that all locoregional lymph nodes need to be microscopically assessed for metastasis.
Biopsy for definitive diagnosis
Squamous cell carcinoma is usually a straightforward histologic diagnosis. The typical histologic characteristics of squamous cell carcinoma include irregular cords of pleomorphic epithelial cells with abundant eosinophilic cytoplasm, prominent intercellular bridges, and keratin pearls.1
Clinical tumor stage can be assessed by using the World Health Organization's TNM (tumor, nodes, metastasis) system (Table 2). The diameter of the primary tumor at its greatest dimension is classified as T1, T2, or T3. Bone invasion (determined radiographically) is described as either a (absent) or b (present). Regional lymph node involvement is categorized as N0, N1, N2, and N3. Distant metastasis is described as either M0 (absent) or M1 (present).5
Feline oral squamous cell carcinoma is an extremely locally invasive, malignant tumor. To date, no therapies or combinations of therapy have shown great success in treating this tumor. Local and regional disease control is the treatment goal. Surgery, radiation therapy, or radiation therapy combined with chemotherapy are the principal treatment modalities used. These treatment options have been widely unsuccessful because of failure of local control. The one-year survival rate is generally less than 10%, with a median survival time of about three months for most therapies.2 A concise and accurate summary of the prognosis for a cat with oral squamous cell carcinoma is not feasible. The literature describing this tumor type consists of mostly small studies involving cats with squamous cell carcinomas of various locations within the oral cavity and a wide range of treatments within those small populations. The following sections summarize the literature addressing therapy for this tumor in cats. Assessing an individual patient's tumor stage and location is critical in advising an owner regarding possible treatment options and likely outcome.
Surgical excision of oral squamous cell carcinoma alone yields high recurrence rates. In eight cats treated with mandibulectomy alone, the median survival time was five and a half months (range five weeks to 12 months); only two of the cats were alive and free of disease at 10 and 12 months.16-18 In one study of 42 cats treated with mandibulectomy for oral neoplasia, 21 of the cats had squamous cell carcinoma, and their median survival time was 217 days, which was significantly shorter than cats with fibrosarcoma or osteosarcoma, whose median survival time was not reached (most of the cats were still alive at the time of calculation).6 One encouraging finding was that survival rates one year after mandibulectomy (43%) were the same as those at two years, implying that cats that lived one year had a good chance for long-term survival. Thirty-eight percent of the cats with squamous cell carcinoma developed local recurrences. For cats that did not have recurrence, the median follow-up time was 169 days; it is possible that more cats would have shown recurrence if their follow-up time had been longer. The high recurrence rate implies that the extent of disease was underestimated at the time of surgery or that it was impossible to obtain adequate clean margins with mandibulectomy.
Ninety-eight percent of the 40 cats that underwent mandibulectomy and survived perioperatively experienced acute morbidity such as dysphagia or inappetence, ptyalism, mandibular drift, and difficulty grooming in the first four weeks after surgery.6 Seventy-six percent of all the cats experienced one or more of these adverse effects for the remainder of their lives. Nevertheless, 83% of owners were pleased with their cats' quality of life and said they would choose this procedure again.6 Thus, mandibulectomy seems to be a reasonable choice for cats with mandibular squamous cell carcinoma, but owners need to be aware of the associated high morbidity.
Surgery is rarely curative when the tumor is located in the caudal region of the oral cavity or when the tumor crosses the caudal midline of the oral cavity.5 In these circumstances, less aggressive palliative surgery for cytoreduction before other therapies such as radiation or chemotherapy may be considered.
Using radiation therapy as the primary treatment for oral squamous cell carcinoma has theoretical advantages compared with other treatment methods,5 including the ability to treat large inoperable tumors and to treat tumors without patient disfigurement. Additionally, regional lymph nodes can be included in the radiation field. A notable disadvantage with radiation as the sole therapy is that bulky tumors tend to exhibit radiation resistance. Additionally, mucositis, which usually develops in the final stages of radiation treatment and generally lasts for one to three weeks after the completion of treatment, can make supportive therapy such as a feeding tube a necessity. Definitive radiation therapy (small, frequent doses) has been reported in a number of settings and is discussed below in those respective areas. The use of palliative radiation and accelerated radiation therapy has been evaluated individually as follows.19,20
One study looked at seven cats with advanced, inoperable oral squamous cell carcinoma.19 The cats were treated with palliative radiotherapy and variable adjuvant chemotherapy with mitoxantrone, piroxicam, or acupuncture. Megavoltage radiation in 8-gray (Gy) fractions was delivered on Days 0, 7, and 21 for a total dose of 24 Gy. While the small sample size makes it difficult to draw definitive conclusions regarding the efficacy of palliative radiation, the fact that six of the seven cats were euthanized because of tumor growth or radiation side effects with a median survival time of only 60 days does not support radiation therapy's use in these patients.19
A pilot study involving an accelerated radiation therapy protocol in eight cats with squamous cell carcinoma was recently reported.20 Over nine days, these cats received seven days of treatment with twice-daily 3.5-Gy fractions for a total dose of 49 Gy. The tumors treated included three lingual tumors, one tonsillar tumor, two mandibular tumors, one cheek tumor, and two large cutaneous lesions; the two cutaneous lesions were in one cat. Treatment fields included the tumor, 1-cm margins, and tumor-draining lymph nodes. Five of the cats were judged to have complete responses, but the survival median for all cats was only 86 days. Overall, the accelerated treatment was well-tolerated by all cats. Despite the poor overall survival time, further studies may be warranted because of the apparent high response rate.20
Chemotherapy and chemotherapy with radiation
Chemotherapy alone has shown minimal effect against oral squamous cell carcinoma in cats. In some studies, chemotherapy has been more successful when combined with radiation therapy.
Doxorubicin and cyclophosphamide. A protocol using doxorubicin and cyclophosphamide had poor efficacy, with only one of five cats with oral squamous cell carcinoma showing a response (partial) to treatment.21 The median survival time of the five cats was 30 days.21
Cisplatin. To date cisplatin, or cis-diamminedichloroplatinum (II), is the most effective chemotherapeutic agent in treating human head and neck squamous cell carcinoma.22 While cisplatin leads to pulmonary vasculitis and death in cats, a second-generation cisplatin analogue, cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) (NDDP), can be liposome-encapsulated (L-NDDP) and safely administered.22 In one study, 18 cats with advanced squamous cell carcinoma disease (World Health Organization's clinical stage II, III, or IV) were treated with L-NDDP at doses ranging from 75 to 100 mg/m2 every 21 days.22 Unfortunately, no clinical responses were seen.
Mitoxantrone and radiation therapy. Mitoxantrone is a dihydroxyquinone derivative of anthracene related to doxorubicin.23 In a study evaluating the toxicity and efficacy of mitoxantrone in cats with malignant tumors, 32 cats with oral squamous cell carcinoma were treated with single-agent mitoxantrone.23 Because of their poor response, 11 cats with squamous cell carcinoma were then treated concurrently with radiation (44- to 65-Gy, 10 to 15 fractions over a three-week period) beginning with the first dose of mitoxantrone (2.5 to 6 mg/m2 ). Four of the cats had sublingual squamous cell carcinoma; the other seven cats had a tumor of the mandible or maxilla. Further information on the stage of the tumors was not provided. None of the cats had signs of toxicosis attributable to the chemotherapy; mucositis consistent with radiation therapy was noted but not described in detail. Eight of the 11 cats went into complete remission (median remission duration of 170 days; range 28 to 485 days), and one cat had a partial remission that lasted 60 days.23 Survival times were not discussed.
While the response rate for combined mitoxantrone and radiation therapy is encouraging, the duration of response is short. As squamous cell carcinoma involving the mandible or maxilla is highly infiltrative into bone, accurate determination of a complete remission is difficult without detailed imaging such as computed tomography. How remission status was determined was not discussed. If only visible gross disease was assessed, the complete remission rate may have been overestimated, contributing to the short duration of remission.
Carboplatin and radiation therapy. Carboplatin chemotherapy plus coarse fractionation radiation therapy evaluated in 11 cats was well-tolerated but only minimally effective.24 While most owners were happy with their cats' quality of life, the few hospital visits, and the cost of this protocol, the median progression-free interval was only 119 days (range of 40 to 245 days) with a median survival time of 161 days.24
Gemcitabine and radiation therapy. Gemcitabine is a pyrimidine analogue with a wide range of antitumor activity against solid tumors.25 In one study, when given in low doses (25 mg/m2 twice weekly) as an adjunctive chemotherapeutic agent to palliative radiation, gemcitabine exhibited potent radiosensitizing effects in vitro and in vivo.25 Each of the eight patients in this study appeared to tolerate the multimodality treatment well with no exacerbation of presenting clinical signs and an overall response rate of 75%. Determination of responses was based on physical examination, thus the response rate may have been overestimated. Additionally, the median duration of remission was only 42.5 days (range 11 to 85 days), with a median survival time of 111.5 days (range 11 to 234 days).25
In another study evaluating the efficacy and toxicity of gemcitabine when given with definitive radiation, 10 cats with oral squamous cell carcinoma were treated with the same gemcitabine dosage (25 mg/m2 twice weekly) in conjunction with radiation given in 3-Gy fractions Monday through Friday with the intent to give a total of 19 fractions.26 Six cats did not complete the radiation course because of local normal tissue toxicosis (e.g. mucositis). Four cats required chemotherapy dose reduction or delay because of unexpected hematologic toxicosis, while two cats had reduction or delay because of other concerns such as inappetence, increased renal values, or anemia.26 The degree of myelosuppression these patients experienced considering the insignificant volume of bone marrow irradiated was surprising, thus the cause of the toxicosis was unclear. Additionally, the antitumor effect was poor, with a median local control time of three months. The degree of toxicosis was such that the authors did not recommend further investigation of this protocol.26
One study evaluated four different treatments in 52 cats with oral squamous cell carcinoma: seven cats were treated with surgery alone, 24 with definitive radiation therapy, 11 with radiation therapy combined with chemotherapy, and 10 with radiation therapy combined with local hyperthermia.5 Radiation was given in 10 to 12 4-Gy fractions on a Monday-Wednesday-Friday schedule. Chemotherapy was low-dose cisplatin (7.5 to 10 mg/m2 intravenously given Monday and Friday), used as a radiosensitizer; no increased toxicosis was seen. Survival times ranged from one to 15 months; the overall median survival time was two months. Cats treated with surgery alone had a median survival time of one and a half months, compared with a median of three months for radiation alone, two and a half months for radiation plus chemotherapy, and two and a half months for radiation plus hyperthermia. No difference in survival rates was found among the treatments. Overall survival of the cats in this particular study was poor, and because of the potentially fatal effects of cisplatin in cats, it is not a recommended treatment option.5
The longest survival time reported to date in cats with oral squamous cell carcinoma was in a small study of seven cats treated with mandibulectomy and adjuvant full-course radiation therapy (five orthovoltage, one cobalt, one combined). All of the cats were stage III, as their tumors were > 4 cm in diameter; one cat had ipsilateral lymph node metastasis. All cats had a gastrostomy tube placed at the time of surgery; the duration of tube usage ranged from three to 44 days (median 15 days). All cats developed mild to moderate tongue lagging postoperatively, and drooling and messy eating were long-term complications. Owners usually bathed their cats' chests and feet at least once a day. No comment was made about owner satisfaction with the procedure. Despite multimodality therapy, six of the seven cats still developed local recurrence, with a median disease-free interval of 11 months. The overall median survival time in this small study was 14 months.4 This survival time is quite lengthy in cats with stage III disease and provides support for further investigation of the use of curative-intent radiation therapy after mandibulectomy for oral squamous cell carcinoma.
Other treatment options
Cyclooxygenase (COX) enzymes catalyze the synthesis of prostaglandins and exist as two isoforms, COX-1 and COX-2. COX-2 is a strong mediator of inflammation and is upregulated in numerous human tumors. An immunohistochemical study looked at COX-2 expression in various feline neoplasms to determine whether COX inhibition may be a potential target for prevention or treatment of tumors in cats.27 COX-2 was found in only 9% of feline oral squamous cell carcinomas and none of the cutaneous squamous cell carcinomas. The absence of COX-2 expression suggests that COX-2 inhibitors will likely have a low potential as an anticancer agent for this tumor type.27
A new strategy emerging in the treatment of cancer is administering agents directed against components of pathways involved in cancer progression. Combining these drugs with conventional treatments such as radiation therapy and chemotherapy may lead to improved outcomes. These drugs include tyrosine kinase inhibitors, some of which are directed against the epidermal growth factor receptor (EGFR). EGFR overexpression has been found in 80% to 90% of human head and neck carcinomas and recently was shown to be expressed in 70% of feline oral squamous cell carcinomas.28 Altered EGFR expression may play a role in feline oral squamous cell carcinoma and provides a rationale for possible benefit of EGFR inhibitors in these patients.
Continued research along these avenues is indicated, as cats are excellent natural models for human head and neck squamous cell carcinoma because of similarities in tumor behavior, response to therapy, possible etiologies, and p53 expression.29 Using cats as a natural model for this disease may benefit both cats and people by providing veterinarians with new ways to treat this aggressive cancer and by providing information that may be applied to the human counterpart of the disease.
Supportive care is critical during treatment of cats with oral squamous cell carcinoma. These cats are often in pain and may be in a poor nutritional state because of their tumors. The cautious use of analgesics should be considered in patients suffering from large and bulky tumors; tumors that have ulcerated; or painful metastatic lesions. Although many analgesics are considered extralabel for use in cats, medications such as nonsteroidal anti-inflammatory drugs and opioids may be beneficial in supportive treatment in advanced cases. Adequate nutrition is also critical in supportive care, and the placement of an esophageal feeding tube or gastrostomy tube may be necessary. The goal of these supportive therapies is to maintain the patient in a comfortable and nutritionally healthy state while allowing the chosen therapy time to have effect against the tumor. In the authors' experiences, supportive care alone in these cases extends survival time only minimally.
Local control of feline oral squamous cell carcinoma is poor with currently investigated therapies, including surgery, hyperthermia, chemotherapy, and radiation therapy.2 The overall poor survival times in cats with oral squamous cell carcinoma may reflect the tumor's location, as sublingual and maxillary tumors are rarely resectable, and also the fact that this tumor is often diagnosed late in the course of the disease. Early diagnosis followed by aggressive local treatment and appropriate supportive care is the best way to improve survival times.
Feline oral squamous cell carcinomas grow rapidly, ultimately causing pain and affecting a patient's ability to eat and drink. Ninety percent of cats die within 12 months of initial diagnosis2; almost all are euthanized because of local disease. Untreated, cats with large masses often are euthanized within weeks of diagnosis because of progressive pain and anorexia. Cats with bulky tumors that cannot be widely excised live a median of two to three months with therapies including surgery, radiation, or chemotherapy.5,19,20,21,25 The best prognosis is for cats with mandibular squamous cell carcinoma in which mandibulectomy with or without radiation therapy can be performed; these cats have a median survival time of five to 14 months, with 43% of cats living two years in one study.4,6,16-18
Oral squamous cell carcinoma is a common malignancy in cats that responds poorly to treatment. The ideal approach for management is early diagnosis by using oral examination, radiographic evaluation including advanced imaging techniques, biopsy, and radical surgical excision. Recurrence despite aggressive surgical resection is common, thus multimodality therapy appears to be indicated. Cats that have been treated with mandibulectomy and curative-intent radiation postoperatively have had the longest survival times. Mandibulectomy has a high associated morbidity, but the overall quality of life of the patients was thought to be good by most owners. Current research focuses on delineating the biologic pathways involved in malignant transformation and progression with the hope of improving therapeutic options for cats.
Jennifer J. Marretta, DVM
Laura D. Garrett, DVM, DACVIM (oncology)
Sandra Manfra Marretta, DVM, DACVS, DAVDC
Department of Veterinary Clinical Medicine
College of Veterinary Medicine
University of Illinois
Urbana, IL 61802
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