Cancer of the Gastrointestinal Tract

Section A

Oral Tumors

Julius M. Liptak and Stephen J. Withrow

Collectively, oral cancer accounts for 6% to 7% of canine cancer and is the fourth most common cancer overall.1,2 In the cat, it accounts for 3% of all cancers.³ Oropharyngeal cancer is 2.6 times more common in dogs than cats, and male dogs have a 2.4 times greater risk of developing oropharyngeal malignancy compared to female dogs.^4,5 A male sex predisposition has also been reported for dogs with malignant melanoma and tonsillar squamous cell carcinoma (SCC).^6,7 Dog breeds with the highest risk of developing oropharyngeal cancer include the cocker spaniel, German shepherd dog, German shorthaired pointer, Weimaraner, golden retriever, Gordon setter, miniature poodle, Chow Chow, and Boxer.^6,8,9 In one study, German shepherd dogs and Boxers had a decreased risk of developing oral melanoma.⁹

In dogs, the most common malignant oral tumors are, in descending order, malignant melanoma, SCC, and fibrosarcoma,10–21 although in other studies SCC is more common than malignant melanoma.² SCC is the most common oropharyngeal cancer in cats, followed by fibrosarcoma, which accounts for 13% of feline oral tumors.³ Other malignant oral tumors in dogs include osteosarcoma, chondrosarcoma, anaplastic sarcoma, multilobular osteochondrosarcoma, intraosseous carcinoma, myxosarcoma, hemangiosarcoma, lymphoma, mast cell tumor, and transmissible venereal tumor.^10–24 Tumors or tumorlike lesions of unusual sites, types, and biologic behavior (e.g., tonsillar SCC, tongue, malignancy of young dogs, viral papillomatosis, canine and feline eosinophilic granuloma complex, epulis, inductive fibroameloblastoma, and nasopharyngeal polyps) will be covered at the end of this chapter. A general summary of the common oral tumors is found in Table 22-1.

Table 22-1

Summary of Common Oral Tumors in the Dog and Cat *

SCC, Squamous cell carcinoma; MST, Mean survival time.

^*References 11–21, 28–32, 37, 53, 57–60, 78, 84–86, 104–111.

Pathology and Natural Behavior

The oral cavity is a very common site for a wide variety of malignant and benign cancers. Although most cancers are fairly straightforward histologically, some have confusing nomenclature or extenuating circumstances that warrant discussion.

Malignant Melanoma

In comparison to other malignant oral tumors, malignant melanoma tends to occur in smaller body weight dogs. Cocker spaniel, miniature poodle, Anatolian sheepdog, Gordon setter, Chow Chow, and golden retriever are overrepresented breeds.⁹ A male predisposition has been reported,⁷ but this is not consistent.⁹ The mean age at presentation is 11.4 years.⁹ Malignant melanoma occurs in cats but is uncommon.²⁵

Malignant melanoma can present a confusing histopathologic picture if the tumor or the biopsy section does not contain melanin, and amelanotic melanomas represent one-third of all cases. A histopathologic diagnosis of undifferentiated or anaplastic sarcoma or even epithelial cancer should be viewed with suspicion for possible reclassification as melanoma. Melan A is an immunohistochemical stain with a moderate sensitivity and specificity for the diagnosis of melanoma in dogs and can be used to differentiate melanoma from other poorly differentiated oral tumors and may be helpful in differentiation.⁹

Melanoma of the oral cavity is a highly malignant tumor with frequent metastasis to the regional lymph nodes and then the lungs.7,26,27 The metastatic rate is site, size, and stage dependent and reported in up to 80% of dogs.* The World Health Organization (WHO) clinical staging system for oral tumors in dogs may have prognostic significance in dogs with oral melanoma (Table 22-2).^{7,26,31,36–38} Malignant melanoma is a highly immunogenic tumor, and molecular and immunomodulatory approaches to treatment are active areas of research.^{33,34,39–47} A review of the biology and molecular mechanisms of canine melanoma development and progression is provided in Chapter 19.^48,49

Table 22-2

Clinical Staging (TNM) of Oral Tumors in Dogs and Cats

Data from Owen LN: TNM classification of tumors in domestic animals, Geneva, 1980, WHO.

Squamous Cell Carcinoma

SCC is the most common oral tumor in cats and the second most common in dogs.1,3,18–21 In cats, the risk of developing oral SCC is significantly increased by over 3.5-fold with the use of flea collars and high intake of either canned food in general or canned tuna fish specifically.⁵⁰ Exposure to household smoke increases the risk of oral SCC by twofold in cats,⁵⁰ and although this was not statistically significant, smoke exposure is associated with a significant increase in expression of p53 in SCC lesions compared to cats with oral SCC not exposed to environmental smoke.⁵¹ For this reason, mutations of p53 may be involved in the development and progression of smoke-related oral SCC in cats.

SCC frequently invades bone in both cats and dogs, and bone invasion is usually severe and extensive in the cat. Increased tumor expression of parathyroid hormone–related protein in cats with oral SCC may play a role in bone resorption and tumor invasion.⁵² Paraneoplastic hypercalcemia has also been reported in two cats with oral SCC.⁵³ Metastasis in the cat is rare and the true incidence is unknown because so few cats have had their local disease controlled; thus an accurate estimate of the metastatic potential has not been confirmed. The metastatic rate for non–tonsillar SCC in dogs is approximately 20%,³² but the metastatic risk is site dependent—the rostral oral cavity has a low metastatic rate and the caudal tongue and tonsil have a high metastatic potential.

Fibrosarcoma

Oral fibrosarcoma is the second most common oral tumor in cats and the third most common in dogs.1,3,18–21,54 In dogs, oral fibrosarcoma tends to occur in large breed dogs, particularly golden and Labrador retrievers; at a younger age, with a median of 7.3 to 8.6 years; and with a possible male predisposition. Oral fibrosarcoma will often look surprisingly benign histologically and, even with large biopsy samples, the pathologist can find it difficult to differentiate fibroma from low-grade fibrosarcoma. This syndrome, which is common on the hard palate (Figure 22-1) and maxillary arcade between the canine and carnassial teeth of large-breed dogs, has been termed histologically low-grade but biologically high-grade fibrosarcoma.⁵⁴ Even with a biopsy result suggesting fibroma or low-grade fibrosarcoma, the treatment should be aggressive, especially if the cancer is rapidly growing, recurrent, or invading bone. Fibrosarcoma is locally invasive but metastasizes to the lungs and occasionally regional lymph nodes in less than 30% of dogs.^{10,18–21,32}

Figure 22-1 A histologically low-grade but biologically high-grade fibrosarcoma in the palate of a golden retriever. The tumor appears circumscribed and benign, but aggressive surgical resection and possibly postoperative radiation therapy (RT) are required for local tumor control.

Epulides

Epulides are benign gingival proliferations arising from the periodontal ligament and appear similar to gingival hyperplasia (Figure 22-2). Three types of epulides have previously been described in the dog: acanthomatous, fibromatous, and ossifying.^56–58 However, the terminology for these tumors has changed; acanthomatous epulis is now termed acanthomatous ameloblastoma and peripheral odontogenic fibroma is the preferred nomenclature for fibrous and ossifying epulides.⁵⁹

Figure 22-2 Typical appearance of a peripheral odontogenic fibroma. The mass is firmly adhered to the underlying bone but does not invade bone. Conservative resection with cautery was curative in this dog.

Peripheral Odontogenic Fibroma

Epulides are relatively common in dogs but rare in cats. Multiple epulides have been described in cats with 50% of cases occurring in cats younger than 3 years.⁵⁵ The mean age at presentation for dogs with peripheral odontogenic fibromas is 8 to 9 years, and a male predisposition has been reported in one study.^57,58 Peripheral odontogenic fibromas are slow-growing, firm masses that are usually covered by intact epithelium. They have a predilection for the maxilla rostral to the third premolar teeth.^58,59

Acanthomatous Ameloblastoma

Acanthomatous ameloblastoma has an aggressive local behavior and frequently invades bone of the underlying mandible or maxilla. Shetland and Old English sheepdogs are predisposed.57,58 The mean age at presentation is 7 to 10 years, and a sex predisposition is unlikely with three studies reporting conflicting results.^57,60,61 The rostral mandible is the most common site.⁶⁰ They do not metastasize. Acanthomatous ameloblastoma is the preferred term, but some pathologists will refer to these tumors by their previous terminology of acanthomatous epulis or adamantinoma.⁵⁶

History and Clinical Signs

Most cats and dogs with oral cancer present with a mass in the mouth noticed by the owner. Cancer in the caudal pharynx, however, is rarely seen by the owner, and the animal will present for signs of increased salivation, exophthalmos or facial swelling, epistaxis, weight loss, halitosis, bloody oral discharge, dysphagia or pain on opening the mouth, or occasionally cervical lymphadenopathy (especially SCC of the tonsil).18–21,62 Loose teeth, especially in an animal with generally good dentition, should alert the clinician to possible underlying neoplastic bone lysis (Figure 22-3), especially in the cat.⁶³ Although paraneoplastic syndromes associated with oral tumors are rare, hypercalcemia has been reported in two cats with oral SCC⁵¹ and hyperglycemia in a cat with a gingival vascular hamartoma.⁶⁴

Figure 22-3 An intraoral radiograph of the rostral mandible of a dog with an acanthomatous ameloblastoma. Note the bone lysis and loosening of the incisor teeth.

Diagnostic Techniques and Work-Up

The diagnostic evaluation for oral cancers is critical due to the wide ranges of cancer behavior and therapeutic options available. If the tumor is suspected of being malignant, thoracic radiographs and lymph node cytologic assessment can be performed prior to biopsy. The most likely cancers to metastasize visibly on thoracic radiographs at the time of diagnosis are melanoma and SCC of the caudal oral, pharyngeal, and tonsillar area. Most animals will require a short general anesthesia for careful palpation, regional imaging, and a biopsy.

Cancers that are adherent to bone, other than peripheral odontogenic fibromas, should have regional radiographs taken under general anesthesia. Regional radiographs include open mouth, intraoral, oblique lateral, and ventrodorsal or dorsoventral projections.⁶⁵ Bone lysis is not radiographically evident until 40% or more of the cortex is destroyed (Figure 22-4). However, apparently normal radiographs do not exclude bone invasion. This evaluation will assist in determining clinical staging information and the extent of resection when surgery is indicated. Computed tomography (CT) or magnetic resonance imaging (MRI) can be a very valuable staging tool, especially for evaluation of bone invasion and possible tumor extension into the nasal cavity or in the caudal pharynx and orbit, and is preferred to regional radiographs when available (Figure 22-5).⁶⁶

Figure 22-4 An intraoral radiograph of the rostral mandible of a cat with a SCC. Note the extensive, ill-defined bone lysis that is very common in cats with this type of tumor.

Figure 22-5 A CT image of a dog with a maxillary fibrosarcoma. Advanced imaging allows better planning of surgery and radiation therapy (RT) because the extent of bone involvement and extension into the nasal cavity is often much greater than can be appreciated grossly.

Regional lymph nodes should be carefully palpated for enlargement or asymmetry. However, caution should be exercised when making clinical judgments of whether neoplastic involvement of regional lymph nodes is present. Lymph node size is not an accurate predictor of metastasis. In one study of 100 dogs with oral melanoma, 40% of dogs with normal-sized lymph nodes had metastasis and 49% of dogs with enlarged lymph nodes did not have metastasis.²⁷ The regional lymph nodes include the mandibular, parotid, and medial retropharyngeal lymph nodes; however, the parotid and medial retropharyngeal lymph nodes are normally not palpable.⁶⁷ Furthermore, only 55% of 31 cats and dogs with metastasis to the regional lymph nodes had metastasis to the mandibular lymph node.⁶⁸ Lymphoscintigraphy or contrast-enhanced ultrasonography can be used to detect the sentinel lymph nodes and guide lymph node aspirates.⁶⁹ Lymph node aspiration should be performed in all animals with oral tumors, regardless of the size or degree of fixation of the lymph nodes.^27,68 En bloc resection of the regional lymph nodes has been described and, although the therapeutic benefit of this approach is unknown, it may provide valuable staging information.^67,68 Based on these diagnostic steps, oral tumors are then clinically staged according to the WHO staging scheme (see Table 22-2).³⁶

The last step, under the same anesthesia, is a large incisional biopsy. Cytologic touch or aspiration preparations of oral tumors are usually not rewarding because of the necrosis and inflammation that commonly accompanies these cancers. Dogs with exophytic or ulcerated masses will generally tolerate a deep wedge or core punch biopsy without general anesthesia. Biopsy is recommended to differentiate benign from malignant disease, for owners basing their treatment options on prognosis, and when other treatment modalities such as radiation therapy (RT) are being considered. Oral cancers are commonly infected, inflamed, or necrotic, and it is important to obtain a large specimen. Electrocautery may distort the specimen and should only be used for hemostasis after blade incision or punch biopsy. Large samples of healthy tissue at the edge and center of the lesion will increase the diagnostic yield, but care must be taken not to contaminate normal tissue, which cannot be removed with surgery or included in the radiation field. Biopsies should always be performed from within the oral cavity and not through the lip to avoid seeding tumor cells in normal skin and compromising curative-intent surgical resection. For small lesions (e.g., epulides, papillomas, or small labial mucosal melanoma), curative-intent resection (excisional biopsy) may be undertaken at the time of initial evaluation. For more extensive disease, waiting for biopsy results to accurately plan treatment is strongly encouraged.

Therapy

Surgery

Surgery and RT are the most common treatments used for the local control of oral tumors. Surgical resection is the most economic, expeditious, and curative treatment. The type of oral surgery depends on tumor histology and location. Except for peripheral odontogenic fibromas, most oral tumors have some underlying bone involvement and surgical resection should include bony margins to increase the likelihood of local tumor control. More aggressive surgeries such as mandibulectomy, maxillectomy, and orbitectomy are generally well tolerated by cats and dogs. These procedures are indicated for all aggressive and/or invasive oral tumors, particularly lesions with extensive bone invasion, with poor sensitivity to RT, or that are too large for cryosurgery (Tables 22-3 and 22-4).^{11–21,70–73} Margins of at least 2 cm are necessary for malignant cancers such as SCC, malignant melanoma, and fibrosarcoma in the dog. If possible, SCC in the cat should be treated with surgical margins greater than 2 cm because of high local recurrence rates. Bone reconstruction following bony resection has been described but is rarely necessary.^13,74–76 Rostral and segmental resections (e.g., mandibulectomy and maxillectomy) may be sufficient for benign lesions and rostral SCC in dogs. Rim resections with a biradial oscillating saw, in which the ventral cortex of the mandible is preserved, may be possible for small benign tumors localized to the alveolar margin of the mandible (Figure 22-6).⁷⁷ Larger resections, including hemimandibulectomy, hemimaxillectomy, orbitectomy, and radical maxillectomy, are necessary for more aggressive tumors, especially fibrosarcoma, and malignant tumors with a more caudal location.^{11–21,70–72} Although these large resections carry some morbidity, owner satisfaction with the cosmetic and functional outcomes is in excess of 85%.^{11–21,71,73,78} Cosmesis is usually very good following most mandibulectomy and maxillectomy procedures (Figure 22-7) but can be challenging with aggressive bilateral rostral mandibulectomies and radical maxillectomies.^{11–21,70–72} Blood loss and hypotension are the most common intraoperative complications, particularly during caudal or aggressive maxillectomy procedures.^19,71 Postoperative complications include incisional dehiscence, epistaxis, increased salivation, mandibular drift and malocclusion, and difficulty prehending food, particularly after bilateral rostral mandibulectomy caudal to the second premolar teeth.^{13–21,53,71} Elastic training, consisting of an orthodontic elastic rubber chain between an orthodontic button on the lingual aspect of the intact mandible tooth and buccal aspect of the maxillary fourth premolar tooth, has been described to maintain occlusion and prevent mandibular drift following mandibulectomy in dogs.⁷⁹ Enteral feeding tubes are not usually required following oral surgery in dogs; however, they are recommended for cats treated with any type of mandibulectomy because eating can be difficult for 2 to 4 months following surgery.^53,78

Table 22-3

Various Mandibulectomies

Table 22-4

Various Maxillectomies

Figure 22-6 A rim resection has been performed for removal of an acanthomatous ameloblastoma with 1-cm margins. Note that the ventral cortex of the mandible has been preserved. Preservation of the ventral cortex prevents the development of mandibular drift and malocclusion.

Figure 22-7 The typical appearance of a dog 6 months postoperatively after subtotal unilateral mandibulectomy for an osteosarcoma. The tongue will often hang out and the remaining hemimandible will drift towards the resected side.

Local disease control is the goal of treatment for most animals with oral tumors. Regional lymph node resection has been described in cats and dogs; although it adds to clinical staging information, its effectiveness in controlling local and metastatic disease is unknown.67,68

Cryosurgery may be indicated for lesions less than 2 cm in diameter that are fixed or minimally invasive into bone. Larger lesions should generally be surgically resected. More extensive lesions in bone will often result in a fracture (mandible) or oronasal fistula (maxilla) if aggressively frozen. Cancer of soft tissue only should be surgically excised and not frozen.

Radiation Therapy

RT can be effective for locoregional control of oral tumors. RT can be used as a primary treatment, with either palliative or curative intent, or as an adjunct for incompletely resected tumors or tumors with an aggressive local behavior, such as oral fibrosarcoma. Malignant melanoma, canine oral SCC, and some benign tumors, such as the acanthomatous ameloblastoma, are known to be radiation responsive, and RT should be considered in the primary treatment of these tumors.31–33,80,81 For canine oral SCC, dental tumors, and fibrosarcoma, daily and alternate day protocols have been described consisting of 2.7 Gy to 4.2 Gy per fraction with a total dose ranging from 48 Gy to 57 Gy.^32,82 Tumor control is better for smaller benign and malignant lesions (T1 and T2 tumors) treated with radiation alone.^31,32,80 Local tumor control and survival time may be improved by combining RT with surgery and/or chemotherapy, especially for tumors considered radiation resistant, such as canine oral fibrosarcoma and feline oral SCC.^53,83–88 Radiation sensitizers, such as etanidazole and gemcitabine, may improve response rates in cats with oral SCC, and platinum drugs have been used as radiation sensitizers in dogs with oral melanoma.^{28,37,84,87,88} However, gemcitabine is not recommended as a radiosensitizer in cats because of significant hematologic and local tissue toxicities.⁸⁹

Oral melanoma is moderately responsive to coarse fractionation protocols. Four different hypofractionated radiation protocols have been described: (1) three weekly 8- to 10-Gy fractions for a total dose of 24 to 30 Gy,30,37 (2) four weekly fractions of 9 Gy for a total dose of 36 Gy,^31,37 (3) six weekly 6-Gy fractions for a total dose of 36 Gy,²⁸ and (4) eight weekly 6-Gy fractions for a total dose of 48 Gy.⁹⁰ In humans, the effect of total radiation dose is controversial, but fraction size does have an impact on response rates. Doses greater than 4 Gy per fraction are recommended as response rates are significantly better with fractions greater than 8 Gy compared to less than 4 Gy.⁹¹ However, in one study of dogs with oral melanoma comparing two hypofractionated protocols of 9 to 10 Gy per fraction to a fully fractionated protocol of 2 to 4 Gy per fraction, there were no significant differences in either local recurrence rates or survival time.³⁷ Coarse fractionation of oral melanoma has also been described in five cats with limited success, including one complete response and two partial responses.²⁵

Acute effects are common but self-limiting. These include alopecia and moist desquamation, oral mucositis, dysphagia, and ocular changes, such as blepharitis, conjunctivitis, keratitis, and uveitis.32,80,92–94 The acute effects of coarse fractionation are less than experienced with the full-course protocols used for oral SCC and dental tumors and usually resolve rapidly.³¹ Late complications are rare, occurring in less than 5% of cases, but can include permanent alopecia, skin fibrosis, bone necrosis and oronasal fistula formation, development of a second malignancy within the radiation field, keratoconjunctivitis sicca, cataract formation, xerostomia, and retinal atrophy.^32,61,80,95 Orthovoltage radiation may be associated with a higher incidence of second malignancies and bone necrosis than megavoltage irradiation.^32,61,80

Hyperthermia offers no advantage over cryosurgery or surgery if it is used alone. In fact, bone penetration is less reproducible with heat versus cold treatment. Hyperthermia at moderate temperatures (42 to 43°C) has been used as an adjunct to irradiation.29,96,97

Chemotherapy

The major problem with most oral tumors is control of local disease. However, chemotherapy is indicated for some tumors with higher metastatic potential, especially oral melanoma in dogs and tonsillar SCC in cats and dogs. Expression of cyclooxygenase 2 (COX-2) has been noted in feline oral SCC ⁹⁸; however, nonsteroidal antiinflammatory drugs (NSAIDs) such as piroxicam have not been effective in the management of this disease in cats in preliminary studies.⁹⁹ Piroxicam does appear to have some effect against oral SCC in dogs,¹⁰⁰ and response rate is improved when piroxicam is combined with either cisplatin or carboplatin.^101,102 Liposome-encapsulated cisplatin is not effective in cats with oral SCC,¹⁰³ but mitoxantrone, in combination with RT, has shown some potential in a limited number of cats with good local responses and durable remission.^85,86

The platinum drugs show the most promise, albeit modest, in treating dogs with oral melanoma, including intralesional cisplatin ¹⁰⁴ and systemic carboplatin.¹⁰⁵ Measurable responses to melphalan have also been reported.¹⁰⁶

Malignant melanoma is a highly immunogenic tumor. The use of immunomodulatory agents is an emerging and exciting approach for the adjunctive management of dogs with oral melanoma. A thorough discussion of the immunotherapeutic approach to management of canine melanoma is provided in Chapter 19.

Prognosis

Clinical series of over 500 dogs with various oral malignancies treated with either mandibulectomy or maxillectomy have been described.11–21,70–72 The majority of cases were treated with surgery alone. Unfortunately, the methods of reporting and outcome results vary with each paper, but an attempt to combine cases by tumor type and outcome is shown in Tables 22-5 and 22-6. Overall, the lowest rates of local tumor recurrence and best survival times are reported in dogs with acanthomatous ameloblastoma and SCC, whereas fibrosarcoma and malignant melanoma are associated with the poorest results.^11–21 Most of these reports suggest that histologically complete resection, smaller diameter, and a rostral location are favorable prognostic factors. In two studies of 142 dogs treated with either mandibulectomy or maxillectomy, tumor-related deaths were 10 to 21 times more likely with malignant tumors, up to 5 times more likely with tumors located caudal to the canine teeth, and 2 to 4 times more likely following incomplete resection.^20,21 Rostral locations are usually detected at an earlier stage and are more likely to be resectable with complete surgical margins. Local tumor recurrence is more frequent following incomplete resection, with 15% to 22% and 62% to 65% of tumors recurring following complete and incomplete excision, respectively.^20,21 Recurrent disease negatively impacts survival time because further treatment is more difficult and the response to treatment is poorer.³⁵ Fibrosarcoma continues to have an unacceptable local recurrence rate and needs to be addressed with wider resections or other adjuvant therapies, such as postoperative radiation.⁸² On the other hand, melanoma is controlled locally in 75% of cases, but metastatic disease requires more effective adjuvant therapy, such as RT, chemotherapy, or immunotherapy.

Table 22-5

Postoperative Outcome After Mandibulectomy for Different Tumor Types *

^*References 11–21, 57–60, 124–126.

Table 22-6

Postoperative Outcome After Maxillectomy for Different Tumor Types *

^*References 11–21, 56–58, 119–121.

For dogs treated with megavoltage radiation, tumor type and tumor size are important factors in local tumor control for both benign and malignant oral tumors. As noted previously, acanthomatous ameloblastoma and SCC in dogs are radiation sensitive. Local recurrence is reported in 30% of oral tumors regardless of treatment, but recurrence is a function of tumor size. Compared to small tumors (T1: <2-cm diameter), recurrence is 3 times more likely in T2 tumors (2- to 4-cm diameter) and up to 8 times more likely in T3 tumors (>4-cm diameter).32,80 Tumor size is also associated with survival in dogs with malignant oral tumors, with 3-year progression-free survival (PFS) rates of 55%, 32%, and 20% for T1, T2, and T3 tumors, respectively.³²