Finding and treating oral melanoma, squamous cell carcinoma, and fibrosarcoma in dogs

The oral cavity is a common site for malignant tumors, accounting for 5% to 7% of all canine cancers.1 The most common oral malignancies in dogs are melanoma (30% to 40%), squamous cell carcinoma (17% to 25%), and fibrosarcoma (8% to 25%),1,2 although the frequency of occurrence varies depending on whether tonsillar squamous cell carcinoma is included in the squamous cell carcinoma category. In three studies analyzing 893 tumors either submitted to a laboratory or entered into a database, squamous cell carcinoma was most prevalent (41%), followed by melanoma (37%) and fibrosarcoma (22%).3-5 These studies included tonsillar squamous cell carcinoma (161 cases). If this category was excluded, melanoma would be most prevalent (46%), with squamous cell carcinoma (28%) and fibrosarcoma (26%) making up the remaining tumors.3-5

Less common malignant oral tumors include osteosarcoma, mast cell tumor, hemangiosarcoma, lymphoma, plasma cell tumor, and multilobular tumor of bone (previously called multilobular osteochondrosarcoma). Other disease processes such as benign tumors, gingival hyperplasia, and infectious conditions can occur within the oral cavity and must be considered as differential diagnoses. Benign tumors such as ossifying and fibromatous epulides and the locally aggressive yet nonmetastatic acanthomatous epulis are not discussed in this article.

SIGNALMENT

Breed

Canine malignant oral tumors can occur in any breed, but certain breeds appear to be overrepresented depending on the tumor's histologic type and location within the mouth. In two studies, melanomas were overrepresented in smaller breeds such as cocker spaniels and miniature poodles,6,7 while in another study lingual melanomas were more common in large-breed dogs.8 Yet other studies show dogs of all sizes being affected by melanoma at any oral location.9-14 Dogs with a heavily pigmented oral mucosa, such as chow chows, have an increased risk of developing melanoma.7-10

Squamous cell carcinoma and fibrosarcoma are more commonly seen in large-breed dogs.1,3,13 While no breed predisposition is noted for gingival squamous cell carcinoma, lingual squamous cell carcinoma may be more common in poodles, Labrador retrievers, and Samoyeds.8,12 Fibrosarcomas also have not been associated with a particular breed, except for the histologically benign, biologically malignant variant (see below) for which golden retrievers are overrepresented.15

Age

The median age reported for melanoma development (11 or 12 years) is slightly greater than that for squamous cell carcinoma (8 to 10 years) or fibrosarcoma (7 to 9 years).3-5,7,9,10,16 One exception is papillary squamous cell carcinoma, which is seen in dogs < 1 year old and has a better prognosis than squamous cell carcinoma does in mature dogs.17,18

Sex

Sex predilection has been variably reported for oral tumors, with older studies reporting a male predominance3-5,7 and more recent studies showing no predilection.8-13,16,19,20

BIOLOGIC BEHAVIOR

Melanoma

The most commonly reported location for oral melanoma is the gingiva or the buccal mucosa (Figure 1), but these tumors may also involve the labial mucosa, palate, and dorsal surface of the tongue.8,21 Melanomas are locally aggressive and highly metastatic, with metastasis to distant locations, including regional lymph nodes (59% to 80%) and lungs (51% to 66%), occurring early in the course of the disease.3,7,9,11,13,16,19,22

While melanomas are generally considered to be uniformly malignant, it has been suggested that tumors originating in the tongue and those classified as histologically low-grade may have less aggressive behavior, although too few cases of lingual melanoma have been reported to draw definitive conclusions.

1. A gingival (buccal mucosa) melanoma involving a dog's caudal mandible and temporomandibular joint region.

Some lingual melanomas are aggressive; in one retrospective study, five of 63 (8%) dogs with oral melanoma had lingual tumors, and location did not impact survival.23 In two additional studies that included lingual melanoma, four of seven (57%) and five of eight (63%) dogs died of their disease.12,24 Interestingly, a grading system correctly predicted a poor outcome in five of five dogs with high-grade tumors and positive outcomes in two of three (67%) dogs with low-grade tumors.24 Another study reviewed 1,196 lingual biopsy reports, and roughly half of the specimens were neoplastic. Melanomas accounted for 23% of the tumors found, with 18 of 148 (12%) showing rare to no criteria of malignancy, but this study did not follow up on case outcomes.8

Histologic grade did correlate with outcome in a recent study describing histologically well-differentiated melanocytic neoplasms from the lips or oral cavity (no lingual tumors were noted).25 Sixty-one of 64 (95%) dogs were alive at the end of this study or had died of unrelated causes, with a median follow-up time of 34 months. Thus, while most oral melanomas are extremely aggressive, histologic grading may identify a small subset, possibly including lingual melanomas, that is less metastatic.

Squamous cell carcinoma

Oral squamous cell carcinoma occurs most commonly in the gingiva, particularly rostral to the canine teeth.3 Squamous cell carcinoma is locally aggressive; however, unlike oral melanoma, metastasis tends to occur infrequently (10% to 20% of cases) and late in the disease course.3,26 The exception is tonsillar squamous cell carcinoma, which metastasizes early, especially to regional lymph nodes.3 Most dogs with tonsillar squamous cell carcinoma have regional nodal metastasis at diagnosis.27,28 In one study, 35 of 48 (73%) dogs with the tonsillar form had regional lymph node involvement noted at necropsy, and 20 of 48 (42%) of the dogs developed widespread distant metastasis, including the lungs, thyroid gland, spleen, liver, mediastinal lymph nodes, kidney, and skeleton.3,27

Lingual squamous cell carcinomas (Figure 2) have a biologic behavior intermediate between that of gingival and tonsillar tumors, with four of 31 (13%) dogs in two studies showing regional nodal metastasis at diagnosis, and another 29% developing metastasis later, mostly to regional lymph nodes.12,29

2. Lingual squamous cell carcinoma that has eroded completely through the midbody of the tongue on the left side.

Fibrosarcoma

Fibrosarcomas are most commonly seen in the maxilla (Figure 3) but can also affect the mandible.15 These tumors are locally invasive with a low metastatic rate. An aggressive variant of fibrosarcoma has a benign appearance histologically yet an extremely aggressive local behavior. This disease is referred to as histologically low-grade but biologically high-grade fibrosarcoma.15,30 A histologic diagnosis of nodular fasciitis, fibroma, granulation tissue, or chronic inflammation in a rapidly growing, locally invasive and destructive oral lesion is supportive for the low-high fibrosarcoma type.15 Both variants of fibrosarcoma have a metastatic rate of around 10% to 20%.3,15

3. A dog with an expansile, proliferative, and ulcerated fibrosarcoma of the rostral maxilla.

CLINICAL SIGNS

Clinical signs in animals with an oral mass can vary. The patient may present after an owner has identified a mass. If the mass is small or in the caudal aspect of the oral cavity, it may not be noted by the owner and may be found on routine physical examination. Clinical signs other than an oral mass that the owner may report include apparent inappetence or reluctance to eat, dysphagia, ptyalism, halitosis, or hemorrhage from the oral cavity. Loss of a tooth, loose teeth, or recent history of a dental procedure with removal of several teeth should also prompt further oral evaluation.

DIAGNOSTIC APPROACH AND STAGING

Once an oral mass has been identified, a general health screening, including a complete blood cell count, serum chemistry profile, and urinalysis, is appropriate since many patients affected by oral tumors are older and may have concurrent diseases. Additional diagnostic tests, such as lymph node cytology, thoracic imaging, biopsy of the mass, abdominal ultrasonography, and skull and dental radiography, can help you diagnose the tumor type as well as determine the stage of disease by identifying metastasis (Table 1).

World Health Organization Staging for Tumors of the Oral Cavity*

Lymph node cytology

Fine-needle aspiration and cytologic examination of the mandibular lymph nodes is a quick and easy test to screen for local metastasis. Ideally, both lymph nodes are aspirated since rostral tumors and tumors that cross midline (which may be difficult to detect in some patients) will drain bilaterally. Metastatic cells found in the lymph node not only may offer prognostic information but can also help identify the primary tumor.

A recent study that evaluated 100 dogs with oral melanoma determined that lymph node size and palpation cannot be relied on to accurately determine whether disease is present within that lymph node.31 Forty-seven percent of the cases had no cytologic or histologic evidence of metastasis, of which 23 dogs (49%) had enlarged lymph nodes. Conversely, and importantly, 16 of 40 dogs (40%) with lymph nodes that were thought to be normal on palpation did have cytologic or histologic evidence of metastatic disease.31 In another study involving seven cats and 37 dogs with a variety of solid tumors, six out of 27 (22%) of the animals in which lymph nodes were normal-size or only slightly enlarged had metastatic disease identified cytologically.32 The sensitivity of cytologic evaluation of fine-needle aspirates was 100%, and the specificity was 96%, signifying that fine-needle aspiration is a consistent method of assessing the regional lymph nodes.32

Keep in mind that other lymph nodes such as the retropharyngeal and parotid lymph nodes drain the oral cavity and cannot be palpated on examination. These lymph nodes may be affected and are hard to evaluate. Computed tomography (CT) may help in visualizing these lymph nodes, if clinically indicated.33

Thoracic imaging

Three-view thoracic radiographs are part of the staging process to assess for distant metastasis. At the time of oral tumor diagnosis, these radiographic findings are usually normal. One study revealed that only 13.6% of dogs with malignant oral tumors had radiographically detectable pulmonary metastasis at the time of diagnosis.33 Another study of 361 dogs with a variety of oral tumors reported radiographic evidence of pulmonary metastasis at the time of diagnosis in eight of 59 (14%) dogs with melanoma, four of 40 (10%) dogs with fibrosarcoma, two of 24 (8%) dogs with tonsillar squamous cell carcinoma, and one of 35 (3%) dogs with nontonsillar squamous cell carcinoma.3

Despite this low yield, thoracic radiography is easy, affordable, and strongly recommended since the presence of pulmonary nodules greatly changes a patient's prognosis and treatment plan. One reason for the low yield may be the limitations of radiographs to detect an early miliary pattern of lung metastasis. In one study, six dogs with melanoma without evidence of metastasis on thoracic radiographs had evidence of miliary lung nodules at necropsy performed one to 21 days later, which suggests the disease was likely present but not identified on radiographs.3

A CT scan would be a more sensitive way to detect these early metastatic lesions. However, the cost and availability of CT needs to be balanced with the likelihood of finding metastatic disease, and, thus, it may be more indicated for tumors with an ultimately high pulmonary metastatic rate such as melanoma. As the availability of CT increases, thoracic CT may become a more routine part of staging for cancer metastasis in general.

Cytology or biopsy of the tumor

If lymph node aspirates do not provide a definitive diagnosis and thoracic radiographic findings are normal, cytology or, preferably, tissue biopsy of the oral mass can be performed to determine the tumor type. Knowing the tumor type can help owners make treatment decisions based on the tumor's biologic behavior and likely prognosis.

At times, especially with round cell tumors such as melanomas and plasma cell tumors, cytologic examination of the mass can provide valuable diagnostic information. Unfortunately, cytologic diagnosis can be challenging because of secondary inflammation found in conjunction with oral lesions as well as high degrees of cellular anaplasia in some tumors; thus, tissue biopsy with histology is required in most cases.

Biopsies should be performed from within the oral cavity and not through the overlying skin, if possible, to spare unaffected normal tissues that may be needed for surgical reconstruction after tumor excision. A wedge biopsy with a scalpel blade (Figure 4) will generally yield a good sample of a tumor in the oral cavity, but be sure to avoid areas of ulceration or suspected necrosis, and try to get a deeper rather than more superficial section. Alternatively, a 4- to 8-mm Keyes punch or Tru-Cut biopsy needle may provide a good sample. For firm masses extensively involving a jaw bone, a Jamshidi biopsy needle can be used. Before the sample is placed in formalin, make impression smears for possible cytology submission, which may help in difficult–to-diagnose cases. Be sure to keep all cytology slides away from formalin, or the fumes will affect the sample.

4. Proper technique for a wedge biopsy of a left caudal maxillary mass. Note that the section being biopsied is away from the ulcerated and necrotic center of the tumor. Histologic examination revealed a melanoma.

Poorly pigmented, or amelanotic, melanomas are an example of a tumor that can be challenging to diagnose. Cytology can help in some of these cases, and special stains can be used on histologic samples. The immunohistochemical markers Melan A, vimentin, and S-100 protein can help confirm the diagnosis of melanoma in amelanotic variants as well as in poorly differentiated tumors.34 Additionally, since some rare melanomas do not behave malignantly, multiple features have been evaluated to help determine how aggressively oral melanoma will behave. Two such features, mitotic index and nuclear atypia, have been determined to be the most helpful in correlating with clinical outcome.24,25

Abdominal ultrasonography

To further evaluate a patient with an oral mass, abdominal ultrasonography may be recommended. The likelihood of identifying metastatic spread of an oral tumor into the abdomen is low. Oral malignant melanoma can spread to the liver in rare circumstances but this is unlikely if regional lymph nodes and lungs are disease-free.3 The true value of abdominal ultrasonography is as a screening procedure for occult problems that are concurrent with the oral tumor. Evaluating internal organs for abnormalities unrelated to the primary tumor in an older dog before it undergoes aggressive and expensive therapies, such as surgery or radiation, is advisable.

Skull and dental radiography

Skull radiography can be performed to help evaluate neoplastic extent, but because of limitations in the information provided by these radiographs, they have been largely replaced by more advanced imaging modalities. More than half of the tumors arising from or near the gingiva will have evidence of bony lysis on radiographs. Remember that 30% to 50% of the bone must be destroyed before radiographic evidence is noted, so plain films will often underestimate the degree of bony involvement.33,35

Dental radiographs can be performed and are useful for evaluating rostral mandibular tumors but prove more difficult to interpret for more caudally extensive tumors and tumors of the maxilla.

Advanced imaging

Advanced imaging such as CT or magnetic resonance imaging can be performed to best evaluate the extent of tumor burden and bony involvement, with CT providing better information about bone structures. These modalities are especially useful in planning surgical resection or radiation therapy.33 They can also be of benefit in evaluating retropharyngeal lymph nodes, which are difficult to assess by physical examination alone. As discussed earlier, CT may also be used to more closely evaluate the lungs for metastatic disease.

TREATMENT AND PROGNOSIS

While some oral tumors may be treated with a single modality such as surgery, many oral tumors require a combination of treatments that can include surgery, radiation therapy, chemotherapy, and immunotherapy. Treatment options vary based on the type, location, and tumor stage.

Surgery

Surgery is often the first treatment of choice (see the sidebar titled "Prognostic factors and complications associated with surgery").

Melanoma. Surgical removal of an oral melanoma is a primary method of treatment, if possible. However, surgical removal alone is not adequate for treating oral melanoma since most dogs will die of metastatic disease. Dogs treated surgically for tumors that are small (< 2 cm) and without evidence of metastasis live the longest, with a median survival time (MST) of 17 months, compared with 5.5 months in dogs with tumors that are > 2 cm or have lymph node metastasis.36,37

Because of the high percentage of cases with bone involvement, complete tumor excision requires en bloc resection of the tumor and the associated bony structures. Conservative surgery is generally not recommended because of recurrence rates > 70% and a poor MST of three to four months.3,38 However, even with complete local excision, death due to distant metastasis will still occur in most patients.

For example, radical surgeries including mandibulectomies and maxillectomies provide a lower recurrence rate compared with conservative excisions, but MSTs are similar, with most patients succumbing to metastasis.3,11,13,16,36 In three studies evaluating 59 dogs with melanoma treated with mandibular resections, the surgical procedures were well-tolerated.13,16,39 However, the MST of dogs in two of the studies was only eight to 9.9 months, with a mean survival of four months in the third study. Most of these dogs died of metastatic disease.13,16,39

Similar to partial mandibulectomies, hemimaxillectomies for oral melanoma reported in two studies evaluating 37 dogs showed a MST of 7.5 to 9.1 months.11,20 Local tumor recurrence occurred in 21% to 48% of the dogs, so even aggressive excisions may not provide clean margins for maxillary masses. At least half of the dogs' deaths were due to local progression, supporting effective local control as a means to extend survival times.20

A third study evaluating 10 dogs with oral melanoma that were treated with either mandibulectomy (four dogs) or maxillectomy (six dogs) found that local recurrence occurred in only 20% of dogs; however, the survival rate at one year was 0%.22 The results of these studies on mandibulectomies and maxillectomies in dogs with oral melanoma emphasize the importance of adjunctive treatment modalities to control both local disease and distant metastasis to provide a longer survival time.

Squamous cell carcinoma. As a primary treatment modality for mandibular or maxillary squamous cell carcinoma, surgery is associated with a longer MST than for melanoma.

Mandibular or maxillary—In 24 dogs with squamous cell carcinoma treated with partial mandibulectomies, the median disease-free interval was 26 months, with a one-year survival rate of 91%.16 Two additional studies evaluating 16 dogs with stage II or III squamous cell carcinoma treated with mandibulectomies reported a MST of seven to nine months.13,39 These MSTs may be lower because of patients with more advanced disease and a lack of censoring of patients that died of other causes, as only seven of 16 (44%) died of neoplastic disease.

Partial maxillary resection in the control of oral squamous cell carcinoma has also been investigated. One study reported a MST of 19.2 months for seven dogs treated with hemimaxillectomy.20 Another study evaluating six dogs treated with partial maxillectomies found a MST of only 3.5 months, with 83% of dogs dying because of their disease, 50% having local recurrence.11 These studies' discordant results may be due to a low number of cases in each study or differences in the aggressiveness of the treatments provided. A third study showed a one-year survival of 84% in 19 dogs treated with surgery for squamous cell carcinoma; 16 (84%) of these tumors affected the mandible. Local recurrence rate was low at 5%, with 11% developing metastatic disease.22

Overall, it appears that mandibulectomies and, possibly to a lesser extent, maxillectomies can be effective in both decreasing disease recurrence and prolonging MST. In contrast to dogs with melanoma, dogs with squamous cell carcinoma that die of their disease will usually die of local, not systemic, disease.

Lingual—Lingual squamous cell carcinoma can also be treated successfully with aggressive surgery (Figure 5). As far as functionality after surgery, an earlier study reported that 40% to 60% of the tongue can be excised with good patient outcome.29 A more recent report described five dogs with lingual resection of 80% to 100% that had an excellent quality of life after a brief adaptation period.40

5. The same dog as in Figure 2 three months after a partial glossectomy. At this time, the patient was eating and drinking normally.

Only limited reports describe the survival of dogs with lingual squamous cell carcinoma treated surgically. Out of 21 dogs with lingual squamous cell carcinoma in one study, only four cases were treated with surgery alone. Two were euthanized within two months for local recurrence and nodal metastasis, while two lived more than 35 months.12 In another study involving eight dogs treated for lingual squamous cell carcinoma, 50% of the dogs were alive and free of disease, with last follow-up at six, 12, 16, and 27 months postoperatively. Two of the dogs had also received mitoxantrone chemotherapy after surgery.29 Since these studies were conducted in the mid-1980s and early 1990s, respectively, they do not reflect changes in patient care that have occurred recently and, thus, may underestimate survival times in dogs treated for lingual squamous cell carcinoma today.

Tonsillar—Tonsillar squamous cell carcinomas are extremely aggressive locally with an increased rate of metastasis compared with their nontonsillar counterparts. Surgical resection alone is a poor treatment option since most affected dogs have lymph node metastasis at presentation. Additionally, because of tumor location and invasiveness, complete removal of the primary tumor is challenging to impossible. In three dogs, tonsillectomy alone resulted in survival times of one, nine, and 38 days.3 Unfortunately, even with multimodality therapy, the prognosis for tonsillar squamous cell carcinoma remains poor.27,28

Fibrosarcoma. Similar to nontonsillar squamous cell carcinoma, surgery is the primary treatment option for fibrosarcoma. In one study, 19 dogs with fibrosarcoma treated with a partial mandibulectomy alone had a median disease-free interval of 10.6 months, with a one-year survival rate of 50%.16 Twelve of these 19 (63%) dogs died during the course of the study, with 11 of the 12 (92%) having local recurrence.16 Two additional studies evaluated three and 16 dogs with stage III or IV oral fibrosarcoma treated with varying mandibular resections and showed survival times of 16 months (mean) and 11 months (median), respectively.13,39 Local recurrence was 75% in the three-dog study compared with 31% in the 16-dog study. This difference in local recurrence rate may be explained by varying surgical techniques and aggressiveness as well as a small population size in each study.

Resection of maxillary fibrosarcoma has also been evaluated. Twenty-nine dogs with fibrosarcoma treated with partial maxillectomies reported in two studies experienced MSTs of 9.5 to 12.2 months. Seventeen of the 29 (59%) dogs died of their disease, with 14 of the 29 (48%) having local recurrence.11,20 The one-year survival rate of 14 dogs treated surgically for fibrosarcoma (seven mandible, seven maxilla) in a third study was 50%. Local recurrence occurred in 36% of the dogs, and 14% of the cases showed metastasis.22

As a compilation, these studies show that surgical removal of fibrosarcoma is important as a first-line modality, but because of the high percentage of recurrence of local disease, adjunctive therapy such as radiation may be necessary to further prolong survival. However, a recent study evaluated 38 dogs with oral fibrosarcoma, 29 of which were treated with surgery alone.41 The tumors were distributed fairly equally between the mandible and maxilla and also between caudal and cranial locations. This group had a MST of 1,024 days, which was much improved over earlier reports. Better preoperative imaging abilities and improved surgical techniques were theorized to be the reasons behind the improved results.41 Overall, aggressive surgical resection is needed to control oral fibrosarcoma, and radiation therapy may be needed in cases in which such resection is not possible.

Radiation therapy

Large-fraction radiation therapy can be used as a primary treatment option for oral melanoma or for palliation of any oral tumor that is too large to surgically resect. Radiation can also be used in a definitive setting as an adjunct therapy after surgery with incomplete margins.

Melanoma. Previously considered resistant to radiation therapy, melanomas were discovered to be sensitive to large doses, or coarse fractions, of ionizing radiation when used as a primary treatment (Figure 6).9,14,42-44 Patients that underwent coarse fractionation not only had good responses but also had limited to no local radiation reactions. This discovery in dogs was made when patients with large, nonresectable tumors were treated with large fractions of radiation in a palliative attempt. In five studies reporting on 245 dogs with melanoma treated with various large-fraction radiation protocols, the MST ranged from seven to 12 months.9,14,42-44 Overall response rate was reported for 53 dogs in two of the studies and was 77% to 94%, with 53% to 69% having complete responses.42,43

6. The same dog as in Figure 1 two months after coarse-fraction radiation therapy.

One of the five studies evaluated 140 dogs, 92 of which (66%) had macroscopic disease before starting radiation therapy.9 Several different radiation protocols were evaluated, including fractions of 10 Gy weekly for three weeks, 9 Gy weekly for four weeks, or 2 to 4 Gy daily for 12 to 19 total days.9 No significant survival advantage or response was found between these three protocols.

This same study identified three risk factors that affected the prognosis in these dogs: rostral vs. caudal location, microscopic vs. macroscopic disease volume, and the absence vs. presence of bone lysis.9 Dogs with no risk factors (rostral microscopic tumor with no bone lysis) had a MST of 21 months. Survival times decreased with increasing numbers of risk factors with a MST of 11, five, and three months for one, two, and three risk factors present, respectively.9

The longest reported MST without segregating for risk factors (12 months) was found in 39 dogs that had tumor debulking surgery followed by large-fraction radiation in conjunction with low-dose cisplatin or carboplatin for radiation sensitization.44 Whether the surgical debulking or the chemotherapy extended these patients' survival times or whether this is a normal variation with small sample sizes cannot be determined.

These studies reveal that coarse-fraction radiation therapy as a first- or second-line treatment is comparable to surgical resection in terms of local tumor control and survival time in dogs with melanoma.

Squamous cell carcinoma. Radiation therapy is used most commonly as an adjunctive treatment after incomplete surgical removal for nontonsillar squamous cell carcinoma, but it can also be a primary modality if surgery is not an option. A radiation protocol using 4 Gy per fraction for a total of 48 Gy for macroscopic squamous cell carcinoma in 39 dogs provided reasonable local control, without complete remission, with a median progression-free survival of 36 months.19 Another study evaluated 14 dogs treated with megavoltage radiation of 3 or 4 Gy fractions for a total dose between 48 and 57 Gy.45 Six of the 14 dogs had previous surgeries, but all had gross disease at the time of radiation treatment. The MST for all dogs was 15 months. The MST of dogs > 9 years old was 10.5 months vs. 36 months for dogs < 9 years. Age-related complications were suggested as a possible cause of this survival disparity. Because of small case numbers, no other prognostic factors were identified.45

Radiation after surgery for tonsillar squamous cell carcinoma was reported in eight dogs, seven of which had lymph node metastases that were not surgically excised.27 Dogs were treated on a Monday-Wednesday-Friday basis with a total dose ranging from 35 to 42.5 Gy. The MST for these eight patients was 3.6 months.27 Widespread metastasis occurred in all of the cases, supporting the need for systemic therapy as well as local therapy in these cases.

Fibrosarcoma. Fibrosarcomas are, unfortunately, considered relatively radioresistant. A protocol of 4 Gy Monday, Wednesday, and Friday for a total of 48 Gy was used to treat 28 dogs with macroscopic fibrosarcoma and provided a median progression-free survival, without complete remission, of 26 months.19 The median progression-free survival decreased with increasing tumor stage, with T1, T2, and T3 tumors having a median progression-free survival of 45, 31, and seven months, respectively. Thus, larger fibrosarcomas are not only harder to resect but are also less likely to be treated successfully with radiation therapy.

A separate study evaluating the use of radiation at 3 to 4.2 Gy daily for a total of 42 to 57 Gy for microscopic residual tumor after incomplete surgical resection of seven oral fibrosarcomas and one anaplastic oral sarcoma showed a MST of 18 months.30 It is odd that dogs treated for microscopic fibrosarcoma had shorter survival times than those treated for T1 or T2 bulky tumors. The authors of the microscopic residual disease study commented that the behavior of those particular tumors was similar to the aggressive histologically low-grade, biologically high-grade tumors; this variant of fibrosarcoma may be the reason for the disparity in results. Additionally, dogs with fibrosarcoma involving full thickness of the associated bone were excluded from the macroscopic disease study; thus, a selection bias may exist in this study, leading to longer survival times.

Chemotherapy

While surgical and radiation treatment options are helpful in controlling local disease, they offer no benefit in the control of metastatic disease. Tumors associated with high metastatic potential, including oral melanoma and tonsillar squamous cell carcinoma, need an adjuvant form of therapy to increase the overall survival time. As fibrosarcomas are rarely metastatic and tend to be chemotherapy-resistant, chemotherapy does not generally play a role in their management.

Melanoma. Chemotherapy has, in general, been considered ineffective against oral melanoma. The most common chemotherapeutic agent used to treat dogs with melanoma is carboplatin. In a study evaluating 25 dogs with measurable melanomas treated with 300 to 350 mg/m2 carboplatin, an overall response rate of 28% (7/25) was seen, with one complete remission and six partial remissions.46 Twenty of the 25 (80%) dogs had stage III or IV disease. The reported response to carboplatin in dogs with macroscopic disease provides support for the integration of this chemotherapy drug in treating dogs with microscopic disease.

A second study evaluating the MST of dogs treated for oral melanoma without radiographic evidence of pulmonary metastases with four weekly fractions of 9 Gy radiation alone vs. radiation and carboplatin showed no significant difference in survival time with the addition of carboplatin. The MST for dogs treated with radiation alone was 10 months with 10 of 13 (77%) experiencing measurable tumor response. The MST for dogs treated with both radiation and carboplatin was 9.5 months with 13 of 15 (87%) experiencing measurable tumor response.14 Overall, the carboplatin was well-tolerated and resulted in no treatment discontinuations or death. While no clear benefit was seen with carboplatin in dogs with macroscopic disease, the number of dogs in this retrospective study was low, warranting further studies in dogs with microscopic disease.

In 11 dogs treated with cisplatin (50 to 55 mg/m2 ) and piroxicam (0.3 mg/kg once daily) for oral melanoma, two experienced complete remissions for an overall response rate of 18%.47 Seven of 17 dogs treated either for melanoma or squamous cell carcinoma with this protocol developed renal toxicosis, mostly mild to moderate.47 However, in an earlier study of dogs treated with a combination of cisplatin (60 mg/m2 every 21 days) and piroxicam (0.3 mg/kg once daily) for transitional cell carcinoma of the bladder, 12 of 14 dogs developed renal toxicosis, with nine of the dogs having moderate to severe toxicosis.48 The severity of the renal effects in this group of dogs may relate to the slightly increased dose of cisplatin given or the primary cancer being associated with the urinary tract. Regardless, at this time, this combination of drugs is not recommended.

Squamous cell carcinoma. Systemic therapy may be indicated as sole or adjuvant therapy for nonresectable squamous cell carcinoma and tonsillar squamous cell carcinoma. In one study evaluating 17 dogs with bulky squamous cell carcinoma of any oral location treated with piroxicam alone, the overall remission rate was 18%, with one complete remission and two partial remissions.49 In nine dogs with squamous cell carcinoma, two experienced a complete remission and three had partial remissions when treated with cisplatin and piroxicam for an overall remission rate of 55.5%.47 However, concerns with the nephrotoxicity of this protocol (see above) limit its use. An additional study evaluated carboplatin and piroxicam in seven dogs with nontonsillar squamous cell carcinoma and showed complete clinical remission in five of seven (71%) dogs, with a MST of 19.2 months.50 Further study of this potentially promising combination is warranted.

An earlier study of 22 dogs with tonsillar squamous cell carcinoma compared surgery with chemotherapy (three different protocols, none of which included piroxicam) to surgery, chemotherapy, and radiation. Survival times for the first group ranged from two to four months compared with nine months for tri-modality therapy.28 Chemotherapy with carboplatin and piroxicam, with and without radiation therapy, to treat dogs with tonsillar squamous cell carcinoma should be explored.

Immunotherapy

Immunotherapy uses the body's own immune system to identify and kill tumor cells. Since melanoma is an antigenic tumor, many studies have evaluated immunotherapy as a treatment. Tumor regression occurred in five of 13 (38%) dogs treated with human recombinant interleukin-2 and tumor necrosis factor alpha, showing that immunotherapy can have anti-tumor effects.51,52

Another approach to immunotherapy is tumor vaccines. These vaccines are not preventive but therapeutic and work by stimulating the immune system to recognize the malignant cells. One such investigational vaccine, an allogeneic whole-cell tumor vaccine that expresses human glycoprotein 100, developed at the University of Madison-Wisconsin was used in 34 dogs (25 with oral melanoma, eight with nail bed melanoma, and one with cutaneous melanoma) with bulky disease.53 The overall response rate was 17%, with a tumor control rate of > 6 weeks of 35%. As with chemotherapy, responses in dogs with macroscopic disease lend support to the investigation of this therapy in dogs with microscopic disease.

A xenogeneic vaccine that uses human tyrosinase plasmid DNA (Canine Melanoma Vaccine, DNA—Merial) has a conditional license for use in dogs with stage II or III oral melanoma in which local disease control has been achieved.54 The targeted antigen of this vaccine is the tyrosinase glycoprotein, which is involved in melanin production and, thus, found in all melanoma cells. Limited data are published in regard to dogs with melanoma treated with this vaccine. In nine dogs with measurable disease (five with oral melanoma, three with nail bed melanoma, and one with intraocular melanoma), with tumor stages ranging from II to IV, a MST of 13 months was achieved with the vaccine, which was well-tolerated.55 The expected survival time for stage II to IV oral melanoma patients treated with surgery alone ranges from two to five months.23,36,37 The vaccine is given intramuscularly once every two weeks for a total of four treatments, with booster vaccinations recommended every six months, and it is available only through veterinary oncologists or internists.54 Ongoing studies of clinical patients treated with the vaccine will clarify the role and benefit of this new therapeutic.

SUMMARY

The diagnosis and staging of oral malignancies is fairly straightforward. Early detection can be a great advantage in the treatment of all the tumor types, as small size improves resectability and, in dogs with melanoma, decreases the likelihood of early metastatic spread. Local disease is usually the cause of death in nontonsillar squamous cell carcinoma and fibrosarcoma, while metastatic spread and local disease are both concerns in dogs with tonsillar squamous cell carcinoma and melanoma. Prognosis may be predicted by the tumor's type, size, location, and stage at diagnosis. Multimodality therapy that can include surgery, radiation, chemotherapy, and immunotherapy may be applied with varying success, depending on tumor type and location. Many dogs with oral tumors can be successfully managed with appropriate care.

Virginia J. Coyle, DVM

Laura D. Garrett, DVM, DACVIM (oncology)

Department of Veterinary Clinical Medicine

College of Veterinary Medicine

University of Illinois

Urbana, IL 61802

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