Tumors of the Alimentary Tract

Tumors of the Alimentary Tract

John S. Munday,1 Christiane V. Löhr,2 and Matti Kiupel3

1Massey University, New Zealand

2Oregon State University, USA

3Michigan State University, USA


The alimentary tract includes the oral cavity, esophagus, stomach, intestine, and rectum. These structures all share the same basic structure and consist of an epithelial‐lined cavity supported by a submucosa. This submucosa is surrounded by bone in parts of the oral cavity and by muscle in the rest of tract. Because of this consistent basic structure, tumors that develop within the tubular alimentary tract can be subdivided into those of the epithelium and those that develop within the supporting mesenchymal tissue. Tumors of each component tend to occur in similar locations and have similar biological behavior within all the domestic species. The tonsils, tongue, teeth, salivary glands, peritoneum, and pancreas are also included in this chapter. These structures lack the regular arrangement of the tubular alimentary tract and are described in separate sections within the text.

In the previous edition of Tumors in Domestic Animals, the excellent description of tumors of the alimentary tract was written by Drs. Head, Else, and Dubielzig. The current authors would like to pay tribute to the previous authors and acknowledge the important basis for the updated chapter that the previous edition formed. Since the previous edition was published, numerous reports describing the diagnosis and behavior of tumors of the alimentary tract have been published. Particular emphasis has been given in this chapter to recently described immunohistochemical features of tumors, newly established methods to differentiate inflammatory and neoplastic diseases, and prognostic features of neoplasms that can be evaluated by a diagnostic pathologist.

The increased use of immunohistochemistry (IHC) to make a definitive diagnosis is well illustrated by the recent discovery that some gastrointestinal tumors that were believed to be of smooth muscle origin are actually derived from interstitial cells of Cajal. As the cell of origin has been found to influence biological behavior, IHC differentiation is essential for a pathologist to accurately predict prognosis. The use of IHC is also of great value in the diagnosis of oral melanocytic and plasma cell tumors.

Differentiation between inflammation and neoplasia of the gastrointestinal tract is a common diagnostic challenge. New techniques to differentiate feline inflammatory bowel disease and feline intestinal lymphoma have recently been reported and are discussed. Likewise, differentiation between hyperplastic and neoplastic lesions of the teeth, rectum, and mesothelium can be challenging for pathologists and are discussed in the chapter. Unlike the previous edition, rectal tumors are considered a separate entity and are not included with other intestinal neoplasms. This is due to the different presentation of these neoplasms and the accumulating evidence that neoplasms of the rectum show a different clinical course to neoplasms elsewhere in the intestine. Similarly, tonsillar and lingual tumors show significant differences to other oral tumors and are considered separately.

There is much new information describing prognostic indicators and survival times of animals with gastrointestinal neoplasia. Unfortunately due to inter‐study variation in case definitions, clinical staging, or treatment, the results of these studies often lack consistency making it difficult to draw firm conclusions. For this reason, most survival times are reported as ranges within the chapter. Histological or IHC prognostic markers are described, although determining the significance of some markers is difficult due to conflicting data.

In comparison to the domestic species, the biological behavior of human alimentary tumors has been intensively studied and is well defined. As veterinary oncology continues to move closer to human oncology, it is likely that many of the tumor characteristics used to classify, stage, and predict the prognosis of human tumors will be applied to tumors of domestic animals. For this reason, the current classification and staging schemes used in humans are briefly described along with established prognostic indicators for human alimentary neoplasms.

Due to the large number of reports describing alimentary tumors in domestic species and the limited space available, only the key and most recent references are listed.


General considerations

Oral tumors include those of the oral cavity, pharynx, gingiva, dental structures, tongue, tonsils, and salivary glands. Due to significant differences in tumor types or clinical behavior, lingual, tonsillar, odontogenic, and salivary gland tumors are discussed in separate sections within this chapter.

Incidence of oral tumors

Oral neoplasia represents around 5% of all neoplasia in dogs.1 Surveys of oral tumors submitted to diagnostic laboratories revealed that around 65% of canine oral neoplasms were malignant.2–4 However, only 35% of canine oral tumors were malignant in a survey of insurance claims.5 It is possible that this difference was due to more benign‐looking oral tumors being submitted for histology from insured dogs than from non‐insured dogs. Alternatively, the population of insured dogs was younger than the general population and the increased rate of benign tumors could due to age differences in incidence between benign and malignant tumors. A review of surveys of malignant canine oral tumors revealed that melanocytic neoplasms were most common, comprising 30–40% of neoplasms. Squamous cell carcinomas (SCCs) and fibrosarcomas represent 17–25% and 8–25% of malignant neoplasms respectively. Fibrous epuli have been reported to be the most common benign canine oral neoplasm. However, as discussed with odontogenic tumors, this diagnosis may encompass several lesions.

Oral neoplasia is also common in cats, representing 6–10% of all feline neoplasia.6,7 Around 90% of these neoplasms are malignant, with SCCs and fibrosarcomas representing around 60 and 13% of all neoplasia at this site respectively.2,7

Oral neoplasia is less common in horses, with 0–1.1% of equine neoplasms reported to develop in the mouth.8,9 Most equine oral neoplasms are malignant and few benign neoplasms have been reported.3 Over half of equine oral neoplasms are SCCs.

Presumably, as most production animals are slaughtered as young adults, oral neoplasia is generally rare in production animals with only sporadic reports of disease in cattle, sheep, and pigs.10 An exception is seen in cattle that are grazed in pasture containing bracken fern. In a study of 586 neoplasms from cattle that has been exposed to bracken fern, the alimentary tract was the most common place for neoplasm development. In this study, 65 SCCs were reported to involve the oral cavity and oral SCCs comprised 11% of all neoplasms (Figure 13.1).11 Bovine upper digestive tract SCCs are discussed in more detail with esophageal tumors. Exposure to bracken fern was also suspected to have predisposed to a high rate of oral fibrosarcomas observed in sheep in northern England.

Photo of squamous cell carcinoma in the cow’s mouth displaying ulcerated neoplasm with infiltrating surrounding structures.

Figure 13.1 Squamous cell carcinoma, mouth, cow. The neoplasm is ulcerated and is infiltrating surrounding structures. This neoplasm was probably caused by carcinogens in bracken fern.

(Source: Masuda et al., 2011.12 Reproduced with permission of Elsevier.)

Clinical signs and diagnosis of oral tumors

Owners of dogs and cats most frequently become aware of an oral tumor by observing a mass. Other clinical signs can include halitosis, excessive salivation, dysphagia, hemorrhage, displacement or loss of teeth, facial swelling, anorexia, weight loss, or regional lymphadenopathy.

Cytology of fine‐needle aspirates, tissue scrapes, or impression smears may allow differentiation between an inflammatory and a neoplastic oral tumor. A definitive diagnosis of an oral neoplasm can sometimes be made using only cytology. Ulceration of an oral neoplasm can make cytological differentiation between inflammation and neoplasia difficult and multiple aspirates may be required to sample deeper areas of the tumor underlying surface ulceration. Due to high cellular cohesion, aspirates of fibromas and fibrosarcomas often yield low numbers of cells for cytological diagnosis. Although many melanomas can be diagnosed cytologically, neoplasms with little melanin may require histology and IHC for definitive diagnosis.

Heavy sedation or general anesthesia is necessary to aspirate the majority of oral tumors. Immediate microscopic examination allows a biopsy to be performed while the animal remains anesthetized if no cytological diagnosis is possible. Excisional biopsy of small discrete tumors can be curative. Deep wedge biopsies are recommended for larger lesions to allow evaluation of the base of the lesion. This is important as it allows invasion by neoplastic cells to be assessed. Additionally, evaluation of the base will allow differentiation between an ulcerated neoplasm and an inflammatory lesion. Furthermore, cells within the base of the neoplasm are most likely to display diagnostic histological features. Once a definitive diagnosis is made, histology samples can be evaluated morphologically or immunohistochemically for prognostic features and a rational treatment plan can be formulated.

Radiology is valuable in the diagnosis and staging of oral neoplasia. Many oral neoplasms infiltrate bone and the radiographic detection of osteolysis can increase the confidence of a cytologic or histologic diagnosis as well as allowing the invasion by the neoplastic cells to be estimated (Figure 13.2). Evaluating invasion is important for clinical staging as well as indicating the likely margins required for surgical excision. Ultrasonography can be used to evaluate the primary neoplasm and to detect enlargement of regional lymph nodes, although as discussed with staging, the size of the node cannot be used to confirm or exclude metastasis. Newer imaging techniques such as computed tomography are becoming more common in veterinary medicine and provide detailed information on the location, invasion, and spread of the neoplasm. Thoracic radiology to detect the presence of pulmonary metastases may be indicated, and should be considered a requirement in cases of canine oral malignant melanoma.

Radiograph of squamous cell carcinoma of cat demonstrating extensive osteolysis of the mandible (arrowed).

Figure 13.2 Squamous cell carcinoma, cat. This radiograph demonstrates extensive osteolysis of the mandible (arrows).

(Image courtesy of Susanne Stieger‐Vanegas, Oregon State University.)

Classification and staging of oral neoplasia

Staging of a neoplasm is performed by the oncologist and describes the extent and the spread of the neoplasm. Accurate and consistent staging is important to allow comparison between clinical studies performed by different researchers. As more information from such studies in domestic animals becomes available, staging will become increasingly important to determine the most appropriate treatment and to accurately predict prognosis. Staging information that may be provided by the pathologist includes the extent of invasion of surrounding bone by the primary neoplasm and whether or not neoplastic cells are present within regional lymph nodes. The histological grade of the neoplasm is not used to determine the clinical stage of an oral neoplasm. The neoplasm is staged at initial diagnosis and the stage does not change as the disease progresses. If a stage II neoplasm subsequently develops distant metastases, this neoplasm now referred to as a “stage II neoplasm with distant metastases” rather than being reclassified as stage IV.

Human oral SCCs are staged using the Tumor, (regional lymph) Node, and Metastasis (TNM) classification. A modification of the then‐current human TNM classification system was adapted for staging oral neoplasia of dogs and cats in 1980 and is the system currently used by most veterinary oncologists. A disadvantage of this system is the high proportion (around 75%) of canine oral neoplasms that are stage III. Having the majority of dogs in the same stage reduces the ability to detect variation in the prognosis between stages. In addition, stage III describes a wide range of dogs from those with no bone or lymph node involvement to dogs with neoplasms that have caused marked osteolysis and have metastasized to ipsilateral regional lymph nodes. An additional disadvantage of the current staging system is the use of tumor size in classification. Unlike humans, who all have similarly sized oral cavities, dogs have marked breed‐dependent variation in oral cavity size. Using the current classification system all 4 cm diameter neoplasms are classified as grade III; however, a 4 cm tumor in a toy breed dog must have extensive involvement of surrounding tissues and will markedly interfere with function, whereas a similarly sized mass in a giant breed dog could develop without invading surrounding tissue and be subclinical when first observed. Therefore it is likely that there will be variation in survival times reported for stage III neoplasms due solely to the size of the affected dog.

In humans, the criteria used to stage neoplasms are frequently updated as features that more accurately predict prognosis are identified. A significant difference between the most recent human staging system and that used in domestic animals is the classification of all human oral SCCs that have bone involvement as stage IV. Stage IV neoplasms are then subdivided into stages IVA, IVB, and IVC depending on the extent of bone invasion and the presence of metastasis. It is the authors’ opinion that adapting the latest human classification system to stage oral neoplasia of dogs and cats (Table 13.1) would have some significant advantages. First, although 60–70% of malignant oral neoplasms of dogs and cats involve bone and would therefore be classified as stage IV,4,7,13 these neoplasms could then be subclassified by the extent of invasion, reducing the proportion of animals in each stage. Second, as tumor size is not used to classify a stage IV neoplasm, this system will prevent any differences in survival times caused by variability in the size of the canine oral cavity.

Table 13.1 TMN classification and staging of oral neoplasms

Current WHO classification for domestic animals14 a Proposed classification modified from human oral SCCs15
T. Tumor size or involvement
Tis. Carcinoma in situ Tis. Carcinoma in situ
T1. Tumor <2 cm diameter T1. Tumor <2 cm diameter
T1a. No bone invasion
T1b. Bone invasion
T2. Tumor 2–4 cm diameter T2. Tumor 2–4 cm in diameter
T2a. No bone invasion
T2b. Bone invasion
T3. Tumor >4 cm diameter T3. Tumor >4 cm diameter
T3a. No bone invasion
T3b. Bone invasion

T4. Tumor any size with bone infiltration

T4a (lip) invasion of cortical bone, floor of mouth, or skin

T4a (oral) invasion of cortical bone, deep muscle of tongue, maxillary sinus, or skin of face

T4b (lip and oral) invasion of masticator space, pterygoid plates, skull base or encircles internal carotid artery
N. Regional node involvement
N0. No evidence of involvement N0. No evidence of involvement
N1. Movable ipsilateral nodes N1. Metastasis within single ipsilateral node
N1a. Not considered to contain metastases
N1b. Considered to contain metastases
N2. Movable contralateral or bilateral nodes N2. Metastasis within multiple ipsilateral nodes
N2a. Not considered to contain metastases
N2b. Considered to contain metastases
N3. Fixed nodes N3. Bilateral lymph node metastases
M. Distant metastasis
M0. No distant metastases M0. No distant metastases
M1. Distant metastases M1. Distant metastases


I T1 N0,N1a,N2a M0 I T1 N0 M0
II T2 N0,N1a,N2a M0 II T2 N0 M0
Any T
III T1, T2
N0, N1
IV Any T
Any T
N2b or N3
Any N
IVA T1, T2, T3

Any N

IVC Any T Any N M1

a Lip neoplasia in domestic animals is currently classified as T1 <2 cm in diameter with exophytic growth, T2 <2 cm in diameter with minimal invasive growth, T3 >2 cm in diameter or deep invasion present, T4 bone invasion present.

Cancer staging requires assessment of regional lymph nodes for the presence of metastases. In the current classification system of oral neoplasia in dogs and cats, the nodal status is determined by whether the lymph nodes are movable or fixed. However, the gross appearance of a lymph node is an unreliable indicator of the presence of neoplastic cells. In a study of dogs with oral melanomas, only 62% of enlarged lymph nodes were confirmed to contain neoplastic cells. Additionally, neoplastic cells were detected in 40% of nodes that were considered to be of normal size.16 Therefore the authors propose that the nodal status is determined solely by cytology or histology to avoid misclassification. Fine‐needle aspiration has been found to have a sensitivity of 90% for detecting neoplastic cells within a node.17 Although most oral neoplasms metastasize first to the mandibular lymph node, 45% initially metastasize to the parotid or retropharyngeal nodes.17 In humans, the nodal status is additionally subdivided according to lymph node size. To avoid variation when comparing large and small breeds of dogs, the authors propose that the extent of nodal spread of a neoplasm is expressed as N1 if neoplastic cells are detectable by cytology or histology in an ipsilateral node, N2 if they are detected in multiple ipsilateral nodes, or N3 if metastases are detected in nodes bilaterally.

Studies of oral neoplasia in dogs and cat have only inconsistently detected significant differences in survival times between different stages using the 1980 classification. As discussed, this may be due to the wide range of neoplasms classified as stage III, the use of tumor size for classification, and the failure to appropriately assess nodal metastases. Additionally, some investigations of the association between tumor stage and prognosis have included multiple types of malignant oral neoplasia. As the different malignancies of the canine oral cavity show different biological behaviors, it is important that each type of neoplasm is considered separately. Likewise, neoplasms of the same type should be separated when they originate in an area of the oral cavity that is known to influence biological behavior. For example, including tonsillar SCCs in a study of oral SCCs will increase the variation in survival times. Furthermore, only tumors treated using the same methods should be used in studies investigating the influence of stage on prognosis. The application of stringent criteria may reduce the number of cases available for analysis, but will increase the likelihood of detecting a significant association between survival times and clinical stage.

In conclusion, clinical staging is the most powerful prognostic indicator for human oral neoplasia and is a critical part of determining the most appropriate treatment. In the domestic species, clinical staging of oral neoplasia has only inconsistently provided significant prognostic information. If the classification system proposed in Table 13.1 is adopted and oral neoplasms of the same type are compared, this will increase the chances of detecting differences in outcomes (survival times, recurrence rates, rates of metastases, treatment responses) between each stage and will allow more accurate comparison of studies performed at different institutions. Accurate follow‐up data are absolutely critical to all investigations of tumor prognosis, including post‐mortem confirmation of metastases and recurrence.


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Epithelial neoplasia of the oral cavity

Squamous papilloma

Papillomas of the oral cavity can be subdivided into squamous papillomas that are benign neoplasms and viral papillomas that are hyperplastic lesions caused by papillomavirus infection. As discussed with non‐neoplastic oral tumors, a viral papilloma can be identified by the presence of papillomaviral cytopathology such as cells swollen by large quantities of blue‐gray granular cytoplasm and koilocytosis. The absence of such changes favors a squamous papilloma although molecular techniques such as PCR or in situ hybridization are necessary to definitively exclude a papillomaviral etiology.

Canine oral squamous papillomas tend to be solitary lesions in older animals in contrast to the oral viral papillomas that are typically multiple and occur in young dogs. Squamous papillomas have an exophytic growth pattern and are composed of well‐differentiated fronds of epithelial cells that remain confined by the basement membrane and can be supported by a fibrous stalk. The presence of invasion by the cells prompts a diagnosis of papillary SCC. The cause of squamous papillomas is unknown and, although they are expected to persist, there is currently no evidence that squamous papillomas have potential for malignant transformation. Oral squamous papillomas have been rarely reported in cats. In addition, the authors have also observed a similar lesion on the medial surface of the maxilla adjacent to the first molar tooth of a 7‐year‐old saddlebred horse.

Squamous cell carcinomas

General considerations

SCCs are the most common oral neoplasm of cats, horses, and the production animal species. They are the second most common malignant oral neoplasm of dogs. In humans, SCCs represent 95% of all oral neoplasia. Tobacco and alcohol consumption is considered the most common cause of oral SCCs in developed countries. However, poor oral hygiene and an inadequate diet also increase neoplasia risk.1 Infection by papillomaviruses has been reported to cause up to a quarter of human oral SCCs.2 People with an affected close relative are at increased risk, possibly due to genetically inherited differences in the activation and detoxification of carcinogens.1

Gross appearance and cytological diagnosis

In all species, oral SCCs initially appear as pale plaques or irregular roughened raised areas in the oral mucosa. As the neoplasm increases in size, it can either protrude, forming a fleshy mass, or appear as a raised plaque with a central area of ulceration. Invasion by the neoplastic cells can distort surrounding structures and ulceration and secondary infection is likely. As most oral SCCs in domestic animals are advanced when first diagnosed, they most often present as ulcerated raised masses that infiltrate surrounding tissues.

Cytology is useful in evaluating focal ulcerative lesions in the mouth of dogs and cats and allows differentiation between a SCC and an inflammatory lesion such as an eosinophilic granuloma or bacterial stomatitis. However, due to the presence of ulceration and secondary infection it can be difficult to obtain diagnostic samples of an oral SCC. To avoid sampling the surface inflammation, deep scrapes or fine‐needle aspirates are recommended. The cytological appearance of an oral SCC is dependent on the differentiation of the neoplastic cells. Cytology from a poorly differentiated neoplasm reveals a highly anaplastic population of cells with few showing evidence of keratinization (angular cells with increased quantities of pale cytoplasm). In contrast, evidence of malignancy can be difficult to find in well‐differentiated SCCs. Most oral SCCs are intermediate between these two extremes and diagnosis is usually made by the identification of clumps of large angular cells showing variable keratinization. Features of malignancy within the cell population such as high variability in cell and nuclear size and appearance can be used to differentiate neoplastic from dysplastic epithelial cells. Neutrophil emperipolesis is common within oral SCCs and can often be detected cytologically. A cytological diagnosis of SCC is supported by other clinical findings such as radiographic evidence of osteolysis.

Histological diagnosis and subtyping of oral SCCs

Histology of an oral SCC reveals a proliferation of epithelial cells. Depending on the appearance of the cells, oral SCCs can be divided into subtypes. Although few pathologists currently routinely subtype oral SCCs from domestic animals, a study of canine oral SCCs revealed 69 conventional, 5 papillary, 5 basiloid, 3 adenosquamous, and 2 spindle cell SCCs.3 An awareness of the subtypes of SCCs is important for two reasons. First, while histological diagnosis of a conventional oral SCC is generally straightforward, other oral SCC subtypes may represent more of a diagnostic challenge and may require IHC for definitive diagnosis. Second, in humans different oral SCC subtypes show different clinical behavior resulting in differences in prognosis. Currently no studies in the domestic species have investigated whether the subtypes show differences in behavior. However, considering the evidence from human studies, is it probable that subtyping will be found to be of prognostic significance in the domestic species.

Conventional SCCs are the most common subtype of oral SCC in all domestic species and appear as trabeculae and nests of epithelial cells extending into the submucosa (Figure 13.3A) Cells at the periphery of the nests are smaller and more basiloid with cells in central areas larger with eosinophilic cytoplasm. Disorderly maturation of neoplastic squamous cells is visible with keratinized cells interspersed between basilar cells and variable numbers of keratin pearls. Areas that contain solid masses of neoplastic cells are often present. Intercellular bridging is present and is most easily identified using ultrathin sections that are stained with toluidine blue. Most conventional SCCs are highly infiltrative with small clusters or individual cells visible separate from the main neoplasm mass. Neoplasms are often ulcerated with necrosis, neutrophils, and bacteria visible within superficial aspects of the SCC. Often the neoplastic cells can be seen merging with the overlying epithelium; however, as the tumors are infiltrative, cells can be present infiltrating under intact gingival epithelium and a lack of connection to the overlying epithelium does not exclude a diagnosis of SCC. In SCCs that invade bone, osteolysis is visible with nests of cells and increased connective tissue present within the remaining spicules of bone (Figure 13.3B). Scattered clusters of neoplastic cells, often surrounded by lymphocytes, are typically present within surrounding muscle and connective tissue. Rarely, the epithelial cells induce a marked fibrous response. Although cellular pleomorphism can be marked, neoplastic cells are generally large and polygonal with eosinophilic cytoplasm. Giant cells and multinucleate cells can be found scattered within some SCCs. Large neoplastic cells often contain intracytoplasmic neutrophils (emperipolesis).

2 Micrographs (a,b) of squamous cell carcinoma of cat’s mouth illustrating trabeculae and nests of neoplastic cells and residual spicules of invaded bone (arrowhead). Inset: Neutrophilic emperipolesis.

Figure 13.3 Squamous cell carcinoma, mouth, cat. (A) Trabeculae and nests of neoplastic cells are visible. Cells towards the periphery of the trabeculae tend to be smaller and more basal while evidence of keratinocyte maturation and keratinization are visible towards the center. (B) Trabeculae of neoplastic cells (arrow) are visible along with residual spicules of invaded bone (arrowhead) and increased fibrous tissue. Neutrophilic emperipolesis is a common feature in these neoplasms (inset).

Histology usually allows a definitive diagnosis of a conventional SCC. However, differentiation between an inflammatory lesion and a SCC can be difficult in samples that contain predominantly inflammation with only small numbers of anaplastic epithelial cells. This is often encountered when superficial samples of alveolar bone are taken during tooth extraction. Definitive diagnosis can require deeper biopsies so that epithelial cells that are not associated with the inflammation can be adequately evaluated. IHC using cytokeratin can be useful to demonstrate small numbers of epithelial cells infiltrating within small samples that do not contain an identifiable tumor mass. Differentiation between a conventional SCC and an acanthomatous ameloblastoma (formerly acanthomatous epulis) is necessary. Although both contain cords or nodules of epithelial cells, the presence of keratin is more suggestive of a diagnosis of SCC. Poorly differentiated conventional SCCs can contain little keratin. However, the cells within an acanthomatous ameloblastoma remain well differentiated and show features of odontogenic epithelium such as regular palisading. In contrast, the neoplastic cells within a poorly differentiated SCC are irregularly arranged and have marked anaplasia present within the cell population.

Carcinoma in situ appears as a thickening of the oral epithelium due to a proliferation of dysplastic cells that remain confined by the basement membrane. Although all SCCs are thought to initially develop from this subtype, oral in situ carcinomas are rarely recognized in domestic animals.

Verrucous SCCs appear grossly as exophytic cauliflower‐like tumors. Histologically, they are characterized by the presence of broad tongues of mature squamous epithelium that “push” into underlying tissue rather than infiltrating as in conventional SCCs (Figure 13.4A).4 The neoplastic cells typically have little evidence of atypia or other features of malignancy. In humans, verrucous SCCs have a more favorable prognosis than other oral SCC subtypes and are considered to have little, if any, metastatic potential. Verrucous SCCs have been reported in the mouth of a young dog as well as in two older dogs.5 Although surgical excision of one canine verrucous SCC was curative, rapid neoplasm recurrence followed by euthanasia was reported in the two older dogs and it cannot be confirmed that oral verrucous SCCs of dogs and cats have a less aggressive clinical behavior than other SCC subtypes.

6 Micrographs of dog SCC displaying verrucous SCC (a), papillary oral SCC (b), canine basiloid SCC (c), canine spindle cell oral SCC (d), trabeculae of squamous cells (e), and adenoid oral SCC (f).

Figure 13.4 Squamous cell carcinoma (SCC). (A) This verrucous SCC from haired skin of a dog is exophytic with broad tongues of epithelial cells that show little evidence of invasion into deeper tissues. The neoplasm contains large quantities of dense fibrous tissue. (B) This papillary oral SCC from a dog consists of neoplastic cells that are predominantly confined to the epithelium. The neoplastic epithelium is folded and supported by a fibrovascular stalk. Careful examination is required to detect invasion of the basement membrane by the neoplastic cells and allow differentiation from an oral papilloma. (C) The neoplastic cells in this canine basiloid oral SCC are mainly undifferentiated and resemble basal cells. However, careful examination reveals foci of keratinization (arrows). (D) This canine spindle cell oral SCC is comprised of elongated cells that are arranged within whorls and bundles with no evidence of keratinization. Immunostaining using anti‐cytokeratin antibodies (inset) allows differentiation from an oral fibrosarcoma or melanoma. (E) Trabeculae of squamous cells (asterisk) are admixed with foci of glandular differentiation (arrows) in this canine adenosquamous oral SCC. (F) This adenoid (acantholytic) oral SCC from a cat consists of cystic spaces that are lined by neoplastic cells and contain acantholytic cells.

(B–E, Images courtesy of F.J.M. Verstraete and B. Murphy, UC Davis.)

Papillary SCCs have been reported in the oral cavity in dogs and appear as proliferative exophytic friable masses. The neoplastic cells are predominantly confined to the epithelium resulting in marked papillomatous folding (Figure 13.4B). The neoplastic epithelial cells are supported by a fibrovascular stalk and can be basilar in appearance or undergo keratinization resulting in the development of keratin pearls. The key diagnostic feature is the presence of invasion of cells into the underlying submucosa or supporting fibrovascular stalk. Infiltration by the neoplastic cells can be difficult to identify due to the complex filiform architecture of the SCC. However, the presence of infiltration is critical to differentiate a papillary SCC from a squamous papilloma.4 Due to the exophytic nature of this subtype, complete excision is more likely to be possible and this subtype has a more favorable prognosis in people. Currently there is no evidence to suggest that a papillary SCC develops as progression from either a squamous or a viral oral papilloma.

Basiloid SCCs have also been reported in the canine oral cavity and cells within this subtype remain undifferentiated and resemble cells within the basal layer of the epithelium. Keratinization is not prominent although is present in most neoplasms (Figure 13.4C). Neoplastic cells can form solid lobules infiltrating into the underlying submucosa. Cells can palisade around the periphery of the lobules and gland‐like spaces can be present.4 Although the palisading of the cells can appear histologically similar to an acanthomatous ameloblastoma, a basiloid SCC can be differentiated by the predominance of small dark basilar neoplastic cells rather than the larger, more eosinophilic cells present within an acanthomatous ameloblastoma. In addition, cells within a basiloid SCC will generally be more anaplastic than those of an acanthomatous ameloblastoma. Basiloid SCCs have a worse prognosis than conventional oral SCCs in people.

Spindle cell SCCs consist of a proliferation of elongated cells arranged within whorls or bundles (Figure 13.4D). Histological differentiation between a spindle cell SCC and a sarcoma or melanoma can be difficult; however, examination of cells within the infiltrating border of the SCC will often reveal foci of squamous differentiation. Although the IHC detection of cytokeratin expression confirms a diagnosis of SCC, up to a third of human oral spindle cell SCCs do not contain cytokeratin immunostaining.6 In these cases IHC (as described elsewhere in this chapter) to exclude a fibroblastic, neural, or melanocytic origin is required with a failure to detect the expression of any tumor marker considered supportive of a spindle cell SCC. This subtype is associated with a worse prognosis than conventional SCCs in people.4 Oral spindle cell SCCs have been reported in dogs.

Other histological subtypes that have been described in domestic animals include adenosquamous and adenoid (also known as acantholytic) SCCs. Both subtypes are best considered variants of conventional SCCs and are comprised predominantly of infiltrative trabeculae of anaplastic keratinizing epithelial cells. In humans, these two subtypes have a similar biological behavior to conventional SCCs. Adenosquamous SCCs have the additional feature of containing foci of glandular differentiation (Figure 13.4E). Adenoid SCCs contain large spaces that are lined by neoplastic squamous cells and contain acantholytic cells (Figure 13.4F).4 Both subtypes could be mistaken for an oral or salivary adenocarcinoma. Staining with alcian blue to detect the presence of mucosubstances within an adenocarcinoma may help with differentiation. A pseudoangiomatous variant of an adenoid SCC contains prominent blood‐filled clefts and may histologically resemble a hemangiosarcoma. The presence of keratinizing epithelial cells will allow diagnosis of a SCC; however, IHC may be required to definitively exclude a hemangiosarcoma in neoplasms that lack this feature.7

Prognostic indicators of oral SCCs

In humans, the clinical stage of an oral SCC is considered to be the strongest prognostic indicator. Other factors that have been reported to be prognostic include the histological subtype of the SCC, the location in the mouth (rostral neoplasms have a better prognosis), the maximum thickness of the neoplasm, the pattern of invasion of the neoplastic cells, lymphocyte infiltration of the neoplasm, and perineural and vascular invasion by the neoplastic cells.8

Histological evaluation of the degree of keratinization, cellular and nuclear pleomorphism, and mitotic rate can be used to grade conventional oral SCCs into well, moderately, or poorly differentiated. Limitations of histological grading include the heterogeneity present within SCCs (especially important when only small samples are available) and the subjective nature of the assessment. Due to these limitations, the histological grade of a human conventional oral SCC is has not been consistently found to be prognostic.

Numerous antibodies have been investigated as IHC markers of prognosis in human oral SCCs.9 Of these, IHC to detect increased cellular p16CDKN2A protein (p16) is well established to indicate a papillomaviral etiology and a better prognosis.2 Although p16 immunostaining was found to predict prognosis in feline cutaneous SCCs,10 there is little evidence that papillomaviruses cause oral SCCs in domestic animals, suggesting p16 immunostaining will not be prognostic. Antibodies against epidermal growth factor receptor, p53, and matrix metalloproteinases have also been extensively studied in human oral SCCs, although none has been found to consistently predict prognosis.

Prognostic indicators for oral SCCs in domestic animals are less established and are discussed in more detail in the descriptions of canine and feline SCCs. In contrast to human oral SCCs, staging has only inconsistently been associated with survival times in canine and feline oral SCCs. When examining histology samples of oral SCCs it should be determined whether or not the neoplasm has been completely excised. The subtype of the SCC should also be determined. If the SCC is a conventional subtype, the neoplasm can be graded histologically. When a series of 69 conventional canine oral SCCs were graded, 33 were classified as well differentiated, 31 as moderately differentiated, and 5 as poorly differentiated.3 Although there have been few studies to determine whether the histological grade is prognostic, it is possible that the subtype and histological grade may be useful to predict tumor behavior, especially in cases in which complete clinical staging is not possible.

Canine oral squamous cell carcinoma

Location, signalment, and etiology

Canine oral SCCs develop most frequently on the gingiva with the maxillary and mandibular gingiva involved roughly equally (Figure 13.5). Less common locations for canine oral SCCs include the lips (6%), hard or soft palate (3%), and pharynx (2%).11 SCCs of the tongue and tonsil are discussed separately. The average age of dogs with oral SCCs is 9 years with a range of 1.2–14 years.12 Larger dogs develop oral SCCs more frequently than small dogs, and English springer spaniels, Shetland sheepdogs, and German shepherds may be predisposed.3,13 The cause of most canine oral SCCs is unknown, although intraoral radiation therapy may rarely predispose to neoplasm development. As discussed with oral papillomatosis, papillomaviruses do not appear to be a significant cause of canine oral SCCs.

Photo of squamous cell carcinoma in a dog's mouth displaying the neoplasms as a raised plaque with central ulceration and necrosis (arrowed).

Figure 13.5 Squamous cell carcinoma, mouth, dog. The neoplasm appears as a raised plaque with central ulceration and necrosis (arrows).

(Image courtesy of K.G. Thompson, Massey University.)

Biological behavior, treatment, and prognosis

Canine oral SCCs are invasive, with evidence of bone invasion detectable at diagnosis in around 70% of cases. Neoplasms are slow to metastasize, with fewer than 15% of dogs having detectable nodal metastases and fewer than 5% of dogs having radiographic evidence of pulmonary metastases at diagnosis. Due to this slow metastasis, many canine oral SCCs are considered curable. If euthanasia is necessary, this is usually due to pain and dysfunction caused by SCC invasion rather than metastatic disease.11–13 Currently, no associations between the biological behavior and prognosis of a canine oral SCC has been established with SCC subtype, histological grade, or a molecular marker.

There are numerous treatment options for canine oral SCCs, including surgical excision, radiation therapy, chemotherapy, and photodynamic therapy. Surgical excision of the SCC without removing the adjacent bone is often not curative and local recurrence was observed in 5 (63%) of 8 dogs treated this way. These dogs had a median survival time (MST) of 9 months and a 1‐year survival of 38%.12 In comparison, local recurrence was observed in just 2 (8%) of 24 dogs with oral SCCs excised by partial mandibulectomy. In this study 3 of the 24 dogs died of oral SCCs, 2 dogs had local recurrence and metastases, while 1 dog developed metastases without recurrence of the primary neoplasm. Overall, a disease‐free interval of 26 months and a 91% 1‐year survival was reported. Younger dogs had a better prognosis; however, neither the size of the neoplasm nor the presence of bone invasion was significantly associated with survival time.14 Hemimaxillectomy was used to treat oral SCCs in 7 dogs. Two (29%) SCCs recurred and the dogs had an MST of 19.2 months and a 57% 1‐year survival. Neither the size of the SCC nor the location of the SCC within the maxilla had prognostic significance in this study.15

Radiation therapy can be used as a sole treatment or as an adjunct with surgery. When used as a sole treatment MSTs of 9–15 months have been reported.12,16,17 Two studies reported that the age of the dog was prognostic and a rostral location of the tumor was associated with longer survival in one study, but not in another. A study of 39 irradiated oral SCCs reported a median progression‐free time of 36 months with the size of the SCC, but not with the anatomic site of the SCC, the age of the dog, or the presence of bone involvement associated with progression‐free time.18

Small numbers of dogs with oral SCCs have been treated using chemotherapy. Tumor remission was observed in 5 of 9 dogs in one study and 4 of 7 in another.19,20 Photodynamic therapy has also been used to treat canine oral SCCs and no tumor recurrence was observed in 8 of 11 dogs receiving this treatment. One of the dogs treated with photodynamic therapy subsequently developed metastatic disease.21

Overall, these studies suggest that canine oral SCCs are locally aggressive neoplasms that frequently invade bone, but metastasize late in the clinical course. Surgical excision is curative with a potential for long survival times with appropriate treatment of nonresectable SCCs. Due to conflicting data, it is currently unknown whether the age of the dog, size of the tumor, or location of the SCC in the mouth significantly influences prognosis.

Feline oral squamous cell carcinoma

Location, signalment, and etiology

SCCs comprise the overwhelming majority of oral neoplasia in cats and oral SCCs are the fourth most common feline neoplasm.22,23 Feline oral SCCs most commonly develop within the mandibular, maxillary, and sublingual regions and neoplasia develops within these three locations at approximately equal rates.23–25 Sublingual SCCs often develop on the floor of the oral cavity close to the frenulum and can invade the ventral surface of the tongue (Figure 13.6).23 Less commonly, SCCs develop on the hard palate, soft palate, larynx, pharynx, and lip, although each location represents less than 2% of feline oral SCCs.25 The average age for neoplasm development is around 13 years with a range of 1.5–22 years.25 No sex, coat color, hair length, or breed predispositions have been identified.25,26

Photo displaying sublingual squamous cell carcinoma in a cat with infiltration of surrounding structures resulting in significant necrosis.

Figure 13.6 Squamous cell carcinoma, sublingual, cat. Infiltration of surrounding structures has resulted in significant necrosis.

(Image courtesy of K.G. Thompson, Massey University.)

The cause of feline oral SCCs is unknown. Despite the strong association between tobacco use and oral SCCs in humans, exposure to environmental tobacco smoke did not significantly increase oral SCC risk in an epidemiological study of 36 cats.26 Likewise, although papillomaviruses cause human oral SCCs, these viruses are rarely detectable in feline oral SCCs and there is no evidence of a causative association.27,28 Neither feline immunodeficiency virus (FIV) nor feline leukemia virus infection (FeLV) has been shown to significantly increase the risk of oral SCC. Dental disease is a risk factor for human oral SCCs, with tartar, caries and tooth loss all associated with increased neoplasia development.1 As dental disease and tooth loss is ubiquitous in older cats this could be a factor in feline oral SCC development. Canned food has been associated with increased risk of feline oral SCCs.26 As canned food is associated with higher rates of dental disease in cats, this could be the link between canned food and oral SCCs in cats.

Biological behavior

Feline oral SCCs are highly invasive but have a low metastatic potential. In a study of 52 cats with oral SCCs, bone invasion was present at diagnosis in 38 (73%).29 Regional lymphadenopathy was detected in 15 cats, although the presence of nodal metastasis was confirmed microscopically in just 7 (13%) cats. Detectable distant metastases were not present in any cat at diagnosis.29 In a study of 18 feline oral SCCs, bone invasion was present at diagnosis in 9 (50%) of the cats with cytologically confirmed nodal metastases in 5 (28%).30 Feline oral SCCs cause necrosis of surrounding tissues which is often worsened by ulceration and secondary bacterial infection. Cats are almost invariably euthanized due to local disease resulting in anorexia, dysphagia, or dyspnea rather than the development of clinically significant metastases. Hypercalcemia was reported in two cats with SCCs of the mandibular gingiva.

Treatment and prognosis

Survival times in cats with oral SCCs are short with most studies reporting MSTs of 44–60 days and 1‐year survival rates of 5–10%.24,29–31 However, two studies in which oral SCCs were excised by mandibulectomy reported MSTs of 21732 and 420 days33 with SCC recurrence observed in 8 of 21 (38%) cats and a 43% 1‐year survival rate.32 Feline oral SCCs have historically been thought to be poorly responsive to both radiation therapy and chemotherapy. However, there is some evidence that survival times can be extended (MST of 163 days in a group of 31 cats) using accelerated radiation therapy and carboplatin, although no controlled studies have been performed.34

Due to the generally short survival times observed in cats with oral SCCs, few prognostic indicators have been established. Cats with maxillary SCCs were reported in one study to survive longer than cats with SCCs in other locations within the mouth.30 In another study, 9 cats with metastases to multiple lymph nodes or distant metastases had an MST of 24 days, while 35 cats without such metastases had an MST of 90 days, although whether survival times were significantly different was not reported. Several studies reported that neither the size of the SCC nor the location of the SCC in the mouth was associated with survival times.29,30,32 Thirty‐six cats with oral SCCs that had diffuse cyclooxygenase (COX)‐1 immunostaining survived significantly longer than 5 cats with SCCs that had patchy COX‐1 immunostaining.24 A study of 67 cats with oral SCCs revealed that cats with neoplasms with a low Ki67 proliferation index survived significantly longer than those with SCCs that had a high index.31 However, this association was not observed in a subsequent study of 21 cats with oral SCCs.35 No significant association between epidermal growth factor receptor expression and survival was detected in either study.31,35

Equine oral squamous cell carcinoma

The larynx and pharynx are frequent sites of SCC development in horses and affected animals often present due to dysphagia or dyspnea. Equine oral SCCs are invasive and the longest survival time reported in 11 horses with laryngeal and pharyngeal SCCs was 4 months, despite surgical excision being attempted in 3.36 Lymph node metastases were reported in 30% of horses with oral SCCs.

Neuroendocrine carcinomas

Neuroendocrine carcinomas within the oral cavity are rare in the domestic animals. These tumors have previously been referred to as oral carcinoids and oral Merkel cell tumors. As with neuroendocrine carcinomas elsewhere, neoplastic cells are arranged in cell nests supported by a delicate fibrovascular stroma. Individual cells tend to be round with pale basophilic cytoplasm and variably sized oval nuclei. Definitive diagnosis is by IHC (see section on Neuroendocrine carcinomas (intestinal carcinoids)) or by the demonstration of neuroendocrine granules using electron microscopy. In a series of 4 canine oral neuroendocrine carcinomas, surgical excision was curative for 3 tumors with the remaining tumor successfully treated using radiation therapy.37


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  15. 15. Wallace J, Matthiesen, D.T., and Patnaik, A.K. (1992) Hemimaxillectomy for the treatment of oral tumors in 69 dogs. Vet Surg 21:337–341.
  16. 16. Evans, S.M. and Shofer, F. (1988) Canine oral nontonsillar squamous cell carcinoma. Prognostic factors for recurrence and survival following orthovoltage radiation therapy. Vet Radiol 29:133–137.
  17. 17. LaDue‐Miller T, Price, G.S., Page, R.L., and Thrall, D.E. (1996) Radiotherapy of canine non‐tonsillar squamous cell carcinoma. Vet Radiol Ultrasound 37:74–77.
  18. 18. Theon, A.P., Rodriguez, C., and Madewell, B.R. (1997) Analysis of prognostic factors and patterns of failure in dogs with malignant oral tumors treated with megavoltage irradiation. J Am Vet Med Assoc 210:778–784.
  19. 19. de Vos, J.P., Burm, A.G., et al. (2005) Piroxicam and carboplatin as a combination treatment of canine oral non‐tonsillar squamous cell carcinoma: a pilot study and a literature review of a canine model of human head and neck squamous cell carcinoma. Vet Comp Oncol 3:16–24.
  20. 20. Boria, P.A., Murry, D.J., et al. (2004) Evaluation of cisplatin combined with piroxicam for the treatment of oral malignant melanoma and oral squamous cell carcinoma in dogs. J Am Vet Med Assoc 224:388–394.
  21. 21. McCaw, D.L., Pope, E.R., et al. (2000) Treatment of canine oral squamous cell carcinomas with photodynamic therapy. Br J Cancer 82:1297–1299.
  22. 22. Stebbins, K.E., Morse, C.C., and Goldschmidt, M.H. (1989) Feline oral neoplasia: a ten‐year survey. Vet Pathol 26:121–128.
  23. 23. Cotter, S.M. (1981) Oral pharyngeal neoplasms in the cat. J Am Anim Hosp Assoc 17:917–920.
  24. 24. Hayes, A.M., Adams, V.J., Scase, T.J. and Murphy, S. (2007) Survival of 54 cats with oral squamous cell carcinoma in United Kingdom general practice. J Small Anim Pract 48:394–399.
  25. 25. Martin, C.K., Tannehill‐Gregg, S.H., Wolfe, T.D., and Rosol, T.J. (2011) Bone‐invasive oral squamous cell carcinoma in cats: pathology and expression of parathyroid hormone‐related protein. Vet Pathol 48:302–312.
  26. 26. Bertone, E.R., Snyder, L.A., and Moore, A.S. (2003) Environmental and lifestyle risk factors for oral squamous cell carcinoma in domestic cats. J Vet Intern Med 17:557–562.
  27. 27. Munday, J.S., Howe, L., et al. (2009) Detection of papillomaviral DNA sequences in a feline oral squamous cell carcinoma. Res Vet Sci 86:359–361.
  28. 28. Munday, J.S., Knight, C.G., and French, A.F. (2011) Evaluation of feline oral squamous cell carcinomas for p16CDKN2A protein immunoreactivity and the presence of papillomaviral DNA. Res Vet Sci 90:280–283.
  29. 29. Postorino Reeves, N.C., Turrel, J.M., and Withrow, S.J. (1993) Oral squamous cell carcinoma in the cat. J Am Anim Hosp Assoc 29:438–441.
  30. 30. Gendler, A., Lewis, J.R., Reetz, J.A., and Schwarz, T. (2010) Computed tomographic features of oral squamous cell carcinoma in cats: 18 cases (2002–2008). J Am Vet Med Assoc 236:319–325.
  31. 31. Bergkvist, G.T., Argyle, D.J., et al. (2011) Expression of epidermal growth factor receptor (EGFR) and Ki67 in feline oral squamous cell carcinomas (FOSCC). Vet Comp Oncol 9:106–117.
  32. 32. Northrup, N.C., Selting, K.A., et al. (2006) Outcomes of cats with oral tumors treated with mandibulectomy: 42 cases. J Am Anim Hosp Assoc 42:350–360.
  33. 33. Hutson, C.A., Willauer, C.C., et al. (1992) Treatment of mandibular squamous cell carcinoma in cats by use of mandibulectomy and radiotherapy: seven cases (1987–1989). J Am Vet Med Assoc 201:777–781.
  34. 34. Fidel, J., Lyons, J., et al. (2011) Treatment of oral squamous cell carcinoma with accelerated radiation therapy and concomitant carboplatin in cats. J Vet Intern Med 25:504–510.
  35. 35. Yoshikawa, H., Ehrhart, E.J., et al. (2012) Immunohistochemical characterization of feline oral squamous cell carcinoma. Am J Vet Res 73:1801–1806.
  36. 36. Jones, D.L. (1994) Squamous cell carcinoma of the larynx and pharynx in horses. Cornell Vet 84:15–24.
  37. 37. Whiteley, L.O. and Leininger, J.R. (1987) Neuroendocrine (Merkel) cell tumors of the canine oral cavity. Vet Pathol 24:570–572.

Mesenchymal tumors of the oral cavity


Non‐odontogenic oral fibromas are rare in domestic animals. In dogs, 11 fibromas were included in a series of 393 oral tumors. Currently, insufficient canine oral fibromas have been reported to determine the location within the oral cavity in which these tumors most frequently develop. Oral fibromas have not been reported in most retrospective studies of feline oral neoplasia. Both lingual and mandibular fibromas have been reported in cattle.1

Most oral fibromas are detected as an incidental finding. Fibromas are typically solitary, firm, well‐demarcated, pale lesions that bulge into the oral cavity and are covered by non‐ulcerated oral mucosa. As fibromas are poorly cellular, they yield few cells by aspiration and cytological diagnosis can be difficult. Histologically, the cells within a fibroma are well‐differentiated spindle‐shaped cells with dense chromatin and low nuclear‐to‐cytoplasmic ratio. Cellularity is variable and the neoplastic cells are separated by a collagenous matrix. The presence of mitoses, cellular anaplasia, or necrosis is more consistent with a fibrosarcoma than a fibroma. As a general rule, the greater the amount of collagen, the more likely the lesion is a fibroma. Distinction of a fibroma from a well‐differentiated fibrosarcoma is critical in large breed dogs, especially golden retrievers, because of, as discussed with fibrosarcomas, potentially marked differences in biologic behavior. Differentiation of a fibroma from some odontogenic tumors, especially peripheral odontogenic fibroma, may be difficult if odontogenic epithelium is not present. Location away from the dental arcade favors fibroma. As discussed with tumors of bone, oral fibromas also have to be differentiated from ossifying fibroma, fibrous dysplasia, and osteoma. These lesions are all expected to contain variable quantities of bone and the absence of bone is suggestive of a fibroma.


General considerations

Fibrosarcomas are the third most common oral malignancy in dogs and the second most common in cats. Fibrosarcomas are rare in the oral cavity of horses and these neoplasms represented just 2 of 29 equine oral malignancies in one survey.2 No cause of fibrosarcoma development can be identified in most cases in companion animals. In contrast, 9 (12%) oral fibrosarcomas were detected in a survey of 75 tumors from sheep grazing bracken fern. Oral fibrosarcomas have been rarely reported in other surveys of sheep tumors, supporting a causative association between bracken fern and ovine oral fibrosarcoma.3 In sheep, oral fibrosarcomas frequently infiltrate adjacent bone, but metastases are rare and limited to regional lymph nodes. No oral fibrosarcomas were identified in a retrospective study of tumors in cattle that were grazing bracken fern.1

Oral fibrosarcomas are usually solitary, pale lesions that, compared to other oral malignancies, are less likely to be ulcerated (Figure 13.7). In contrast to fibroma, fibrosarcomas are not well delineated and are typically infiltrative with destruction of surrounding tissue present at the time of diagnosis. The resulting osteolysis can be assessed using radiography, ultrasonography, or newer techniques such as computerized tomography, and this is useful for accurate clinical staging of the neoplasm as well as determining necessary surgical margins. If adequate cells can be harvested, cytology may reveal spindle‐shaped cells with variable degrees of cellular atypia. The identification of multinucleate cells and numerous mitoses is more supportive of a diagnosis of fibrosarcoma than fibroma although definitive differentiation is dependent on the presence of an infiltrative growth pattern visible on histology.

Photo of fibrosarcoma in a dog displaying a firm and pale mass, which is not ulcerated.

Figure 13.7 Fibrosarcoma, dog. The mass is firm and pale and is not ulcerated.

(Image courtesy of R.A. Fairley.)

Histology reveals moderately to poorly differentiated large spindle‐shaped cells that are arranged in interlacing bundles separated by small amounts of collagenous matrix (Figure 13.8A). Compared to a fibroma, fibrosarcomas are expected to contain less cellular differentiation and more frequent mitotic figures. Additionally, necrosis is often present within the neoplasm and the presence of an infiltrative growth pattern within the deeper aspects of the mass will confirm a diagnosis of fibrosarcoma. Differentiation between an odontogenic tumor and a fibrosarcoma is usually easy if odontogenic epithelium is visible. However, if no odontogenic epithelium is visible, the location of the mass away from the dental arcade is useful to exclude odontogenic origin. Presence of ossification favors diagnosis of osteosarcoma. Differentiation from an amelanotic or poorly melanotic melanoma dominated by spindle cells can be problematic and may require IHC using melanocytic markers.

2 Micrographs of fibrosarcoma in a dog's mouth with neoplasm of spindle-shaped cells (left) and fibrosarcoma in a golden retriever dog with appearance of the neoplastic cells (right).

Figure 13.8 Fibrosarcoma, mouth, dog. (A) This neoplasm consists of spindle‐shaped cells with large open nuclei with marked anisokaryosis. The cells are embedded in moderate amounts of collagenous matrix and mitotic activity is prominent. (B) This fibrosarcoma from a golden retriever dog had an aggressive clinical behavior despite the well‐differentiated appearance of the neoplastic cells. Differentiation of the cells in a canine oral fibrosarcoma is poorly correlated with clinical behavior.

Canine oral fibrosarcoma

The average age of dogs with oral fibrosarcoma is around 7 years (range 6 months to 16 years) with fibrosarcomas tending to develop in younger dogs than oral SCCs or melanomas.4 These neoplasms have been reported to be most common in male dogs of larger breeds.4 A review of surveys of canine oral fibrosarcomas revealed that they develop most frequently in the gingiva (56–87%) with the hard and soft palate (7–17%), lip and cheek (4–22%), and tongue (<2%) less frequently affected.2,4,5 Fibrosarcomas occur at approximately equal frequency in the mandibular and maxillary gingiva.6

Canine oral fibrosarcomas often invade adjacent bone. At the time of initial diagnosis, infiltration into bone is expected in 68–95% of dogs,4 approximately 20% will have metastases to regional lymph nodes,7,8 and over 10%4 have pulmonary metastases. Necropsy surveys detected metastases in 35% of dogs with oral fibrosarcomas; metastases were more common in distant sites, lung or other organs (23–27%), than in regional lymph nodes (19%).4,9 As with other oral neoplasms, cytological assessment of multiple regional lymph nodes is necessary for accurate clinical staging of canine oral fibrosarcomas.

As discussed further with mesenchymal tumors of the skin and subcutis, a subset of canine oral fibrosarcomas show an aggressive clinical behavior despite the cells appearing histologically to be well differentiated (Figure 13.8B). This subset of oral fibrosarcomas most commonly arises from the maxillary gingiva of large breed dogs. In a study of 25 histologically well‐differentiated oral fibrosarcomas, dogs were 3–13 years of age (median 8 years) at diagnosis. As approximately half of the dogs were golden retrievers, this breed may be predisposed. Within 22 of the 25 dogs that were evaluated radiographically, 16 were found to have osteolysis at diagnosis. Disease progression was subsequently observed in most dogs.7 Disease‐free interval ranged from 2 weeks to 41 months. Eight dogs eventually had metastases to either regional lymph nodes (n = 5) or distant sites (n = 3). Survival times were highly variable, averaging approximately 12 months, but had a wide range, probably in part due to a large variety of treatment approaches taken. Interestingly, all dogs had been previously diagnosed with an inflammatory, benign fibrous proliferative, or well‐differentiated neoplastic lesion at the affected site. Poor demarcation of these tumors makes total excision difficult and it can be hard to accurately identify tumor margins histologically. As canine oral fibrosarcomas can appear well differentiated but have an aggressive clinical behavior, classification of fibrosarcomas into low or high grade (based on cellular differentiation, number of mitotic figures, and necrosis) is not prognostic. Therefore, in addition to histological evaluation of the neoplasm, the breed, size of dog, and location on maxilla (or mandible) should all be considered when suggesting a likely prognosis. The prognosis of a canine oral fibrosarcoma has not been shown to be predicted by clinical staging.

Complete surgical excision is the treatment of choice for canine oral fibrosarcoma. However, a recurrence rate of 50% and a median disease‐free interval of 2 years were reported in a study of dogs with oral fibrosarcomas that histology suggested had been completely excised.10 In dogs in which surgical excision was not considered complete, recurrence rates of 32–80% have been reported with median disease‐free intervals of 1 month,4 3.5 months,11 and 12.5 months.12 A recent study of 29 dogs with both completely and incompletely surgically resected oral fibrosarcomas reported an recurrence rate of 24%, median disease‐free interval of 653 days, and survival rates of 88% and 58% after 1 and 2 years, respectively.12 The apparent improvement of prognosis for these neoplasms appears to be due to better surgical techniques. The use of adjuvant radiation therapy has not been found to significantly alter rates of recurrence or survival times.12 Radiation therapy was not found to be an effective sole treatment for canine oral fibrosarcomas with a disease‐free interval of 3.9 months and an MST of 6.8 months.6

Feline oral fibrosarcoma

Fibrosarcoma is the second most common oral neoplasm of cats.13 The average age of cats with oral fibrosarcoma is around 10 years (range 1–21 years); males and females are equally affected.13 The gingiva is the most common location, followed by the palate, lip, pharynx, and tongue.14 Feline oral fibrosarcomas are more common in the rostral oral cavity than within the caudal parts of the mouth or the pharynx.15 Neoplasms are infiltrative and complete surgical excision is often not possible. Although up to 75% of feline oral fibrosarcomas recur after surgery, these neoplasms have a low metastatic potential and 3 of 6 cats survived 2 years after surgical excision of an oral fibrosarcoma.15

Feline oral sarcoid

Feline sarcoids have been described in the oral cavity of cats, but are more common involving the skin and are discussed with mesenchymal skin tumors. The histology of feline sarcoids is very similar to equine sarcoids and tumors are composed of a proliferative epithelium with rete pegs that project into an underlying mass of spindled cells. The mitotic count is low; less than 4 per 10 400× field and the mass is not encapsulated. Similarly to equine sarcoids that are caused by BPV‐1 or ‐2, evidence suggests that feline sarcoids are also caused by a bovine delta papillomavirus, BPV‐14.16 Unsurprisingly feline sarcoids are more common in cats from rural areas.

Granular cell tumor

This is an uncommon benign tumor of the oral cavity. Granular cell tumors have also been rarely reported in the lung, pharynx and brain.The tumor name is descriptive and does not imply a certain cell of origin or line of differentiation.17 Granular cell tumors can have a variable appearance ranging from dense sheets of round neoplastic cells that have small round nuclei and eosinophilic to amphophilic cytoplasmic granules (Figure 13.9A) to polygonal cells with dark, amphophilic, granular cytoplasm and pale eosinophilic matrix (Figure 13.9B). However, all tumors contain cells with cytoplasmic granules that are periodic acid–Schiff (PAS) positive and diastase resistant. Granules are readily visible using electron microscopy and are most likely secondary lysosomes.18 IHC often provides little additional information with expression of neuron‐specific enolase, cytokeratin, lysozyme, vimentin, i‐antitrypsin, and S100 all variously reported.17,18 Granular cell tumors tend to be well demarcated, non‐encapsulated, and have variable amounts of collagenous stroma.17 Mitotic figures are rare. Most granular cell tumors are benign and surgical excision is curative.

2 Micrographs of (a) granular cell tumor in dog's mouth illustrating cells with eosinophilic cytoplasmic granules in periodic acid Schiff (inset) and (b) polygonal cells with amphophilic granular cytoplasm.

Figure 13.9 Granular cell tumor, mouth, dog. (A) Round cells are arranged in dense sheets and contain eosinophilic cytoplasmic granules that stain with periodic acid Schiff (inset). (B) Cells can also appear polygonal with amphophilic granular cytoplasm.

Oral granular cell tumors are seen most frequently in dogs.17,18 They are most common in the tongue but have also been reported on the lip, palate, and gingiva.17 Dogs have an average age at diagnosis of around 10 years (range 6 months to 17 years) and small breeds of dogs may be predisposed.19 Oral granular cell tumors are rare in cats although tumors of the ventral tongue, palate, and tonsil have been reported in middle‐aged to older cats.17,18 Oral granular cell tumors have not been reported in other domestic animal species.

Oncocytomas, the main histological differential for granular cell tumors, also comprise large round to polygonal cells with abundant cytoplasmic PAS‐positive granules. Both oncocytomas and granular cell tumors can develop in the oral cavity and differentiation using routine histology or IHC is difficult. However, electron microscopy can be used to identify the cytoplasmic granules in an oncocyte as mitochondria. Oncocytomas develop most frequently in the salivary gland and are discussed with salivary gland neoplasia.

Both granular cell tumors and oncocytomas can appear histologically similar to rhabdomyoma.20 Laryngeal tumors that were previously reported as oncocytomas are now known to be rhabdomyomas. IHC to detect myoglobin, alpha‐sarcomeric actin, or other markers of striated muscle should allow identification of muscle differentiation within cells of a rhabdomyoma.

Tumors of muscle

Oral tumors of smooth muscle

Oropharyngeal tumors of smooth muscle are rare in domestic animal, but may be underreported as differentiation from fibroma and fibrosarcoma may prove impossible using H&E‐stained slides alone. Histologically, smooth muscle tumors comprise spindle‐shaped cells arranged in streams and interlacing bundles. Extracellular matrix and cross‐striation are absent. The presence of a uniform population of neoplastic cells that have small nuclei and few mitotic figures is suggestive of a leiomyoma rather than a leiomyosarcoma. IHC to detect the expression of smooth muscle actin can be used to confirm smooth muscle differentiation. Although desmin expression suggests muscle origin, immunostaining can be present in both smooth and striated muscle neoplasms. Absence of actin–myosin bundles (cross‐striations) or collagen fibers on electron microscopy can also be used to confirm a smooth muscle origin of the neoplasm, although this technique is generally not used in a diagnostic setting.

Successful surgical excision of a canine oropharyngeal leiomyoma has been described.21 Recurrence after initial resection of an angioleiomyoma of the palate of a young dog was reported, but this tumor did not recur after subsequent complete excision.

Oral leiomyosarcomas are rarely reported in domestic animals. In dogs, leiomyosarcomas occur in the tongue, gingiva of the rostral maxilla or mandible, upper lip, and soft palate.21

Oral tumors of striated muscle

Oral tumors of striated muscle are uncommon but have been reported in dogs, cats, and horses. They are most frequently located in the tongue and less commonly the laryngopharynx, cheek and gingiva.

Oral rhabdomyomas have only been described in the tongue and laryngopharynx of dogs.20 They are well demarcated and contain few mitotic figures. Rhabdomyomas may appear histologically similar to granular cell tumors or oncocytomas on routine histology,20 but can be differentiated using IHC for myoglobin or other muscle‐specific markers or by the demonstration of actin–myosin bundles by electron microscopy.

As discussed with tumors of muscle, rhabdomyosarcomas can be histologically subdivided into types, and embryonal, alveolar, and pleomorphic rhabdomyosarcoma types have all been reported in the oral cavity of domestic animals. Recognition of the histological subtype aids in making a diagnosis, but has not been shown to influence prognosis. Poorly differentiated rhabdomyosarcomas may lack histologically identifiable cross‐striations and therefore IHC or electron microscopy may be required for diagnosis. Expression of markers of striated muscle varies between and within tumors, recapitulating the progression of differentiation during normal muscle development. Antibodies that can be useful include MyoD, an early myogenic regulating factor, myogenin, myoglobin, and alpha‐sarcomeric actin. However, IHC evidence of a skeletal muscle origin may be difficult to detect in some poorly differentiated rhabdomyosarcomas.

In dogs, oral rhabdomyosarcomas are generally solitary, although one dog developed multiple neoplasms within the oral cavity.22 Rhabdomyosarcomas have been reported in the gingiva, tongue, pharynx, and hard palate. Affected dogs are generally younger than those with other oral neoplasms with many less than 2 years old at diagnosis.23 Most canine oral rhabdomyosarcomas are of the embryonal subtype with alveolar rhabdomyosarcomas less frequently reported.23 Surgical resection is the recommended therapy, although both tumor recurrence and metastases occur.

In a study of 8 equine rhabdomyosarcomas, 2 were in the tongue and 2 in the cheek.24 Surgical excision was curative in all three horses in which it was attempted. Most rhabdomyosarcomas in this study were of the embryonal subtype. A pleomorphic rhabdomyosarcoma was diagnosed in the masseter area of one horse and this subtype has been reported also in the equine tongue. An embryonal rhabdomyosarcoma involving the maxilla and hard palate was described in a goat (Figure 13.10).25

Micrograph of embryonal type rhabdomyosarcoma in a goat's mouth illustrating small cells with cellular borders densely packed without cross-striations.

Figure 13.10 Embryonal type rhabdomyosarcoma, mouth, goat. Small cells with poorly defined cellular borders are densely packed with no visible cross‐striations. Immunohistochemistry was required to confirm muscle origin in this case.

Vascular tumors

Vascular tumors include those of blood vessels and lymphatics. In humans, oral vascular tumors have been associated with environmental carcinogens and infection by human herpesvirus‐8. Canine oral vascular tumors have rarely been associated with inhalation of radioisotopes, but no cause of most oral vascular tumors in domestic animals can be determined.

In dogs, 6 of 469 oral malignancies were reported to be of vascular origin and around 1% of canine vascular neoplasms develop in the mouth.26 Two vascular tumors were identified in a series of 29 feline oral tumors. Tumors of blood vessels that are located close to the mucosal surface may present as bulging, bluish red lesions and may be mistaken as melanocytic. Clinical signs that may also be seen include hemorrhage from the mouth, oral pain, halitosis, ptyalism, dysphagia, and increased respiratory noise.

Cytology of aspirates is almost always unrewarding due to the presence of few neoplastic cells and excessive blood contamination. Additionally, definitive differentiation between non‐neoplastic and benign neoplastic vascular proliferations is generally not possible using cytology.

The histological presentation of vascular tumors represents a continuum from malformation (hamartoma) to malignancy. Young animals are more likely to have a vascular hamartoma with vascular neoplasia more common in older animals. Additionally, the presence of multifocal lesions (angiomatosis) is more consistent with a vascular malformation than a neoplasm, especially in calves. Hemangiomas are subclassified into cavernous hemangiomas that have large, erythrocyte‐filled spaces and often contain fibrin thrombi, capillary hemangiomas that have tightly packed narrow empty vascular spaces, and arteriovenous hemangiomas that have variably sized vascular spaces that resemble arteries, veins, and capillaries.27 Lymphangioma appear architecturally similar but lack erythrocytes in vascular channels. Hemangiosarcomas and lymphangiosarcomas are more cellular and vascular spaces may be slit‐like or imperceptible. Cells are large and plump and show variable cellular atypia often with frequent mitoses. Hemangiosarcomas can be subclassified into epithelioid or spindle cell types. Epithelioid hemangiosarcomas appear as solid masses of polygonal cells and differentiation from an anaplastic carcinoma may not be possible without IHC. In dogs and cats, as IHC using anti‐CD31 antibodies is easier to evaluate than immunostaining for von Willebrand factor or CD34, CD31 immunostaining is currently recommended to confirm a vascular origin.28 The different hemangiosarcoma subtypes have not been associated with different prognoses.26

Benign oral vascular tumors

Benign vascular tumors of the oral cavity are rare in dogs, with both hemangiomas and lymphangioma reported in this location. A 2.5‐year‐old Siamese cat developed multiple benign vascular tumors on the lateral surface of the tongue that were diagnosed as hemangiomas. Benign oral vascular tumors appear to be most common in calves that are less than 6 months old. Nine of ten calves had solitary lesions involving the mandibular gingiva, with multiple lesions involving the tongue and skin observed in the other case.29 Vascular tumors were diagnosed as hamartomas or hemangioma and most histologically appeared capillary with cavernous and solid patterns less frequently observed.

Malignant oral vascular tumors

Oral hemangiosarcomas are seen sporadically in dogs. In a study of canine lingual neoplasia, dogs with hemangiosarcoma had a mean age at diagnosis of 10.8 years (range 4–17 years) with border collies appearing to be overrepresented.19 Oral hemangiosarcomas also occur in cats and adult horses. Additionally, oral, cutaneous, and periarticular vascular lesions that were interpreted as hemangiosarcomas were reported in a 9‐day‐old foal.30 There is currently little information about the biological behavior of oral hemangiosarcomas in the domestic animal species.

Extramedullary plasmacytoma

This is a common oral tumor seen most frequently in dogs. Between 15 and 30% of canine extramedullary plasmacytomas develop in the oral cavity and these neoplasms represent around 5% of all canine oral tumors.31,32 Rarely, dogs may develop plasmacytomas in the oral cavity in addition to other locations on the body.31 One in a series of 9 feline extramedullary plasmacytomas occurred in the oral cavity.33 Although disseminated extramedullary plasmacytomas have been reported in horses, they have not been described in the oral cavity in this species.

Dogs with oral extramedullary plasmacytomas are on average 8 years old (range 1.5–22 years) at presentation.32 Canine oral extramedullary plasmacytomas are reported to be most common on the gingiva, with the tongue, tonsil, hard palate, and lip less frequently affected.31,32 Multiple oral extramedullary plasmacytomas are rare in dogs. Oral extramedullary plasmacytomas appear as protruding, fleshy masses that are often ulcerated. Tumors within the pharynx may lead to dysphagia and gagging. Dogs only rarely develop a monoclonal gammopathy due to an oral extramedullary plasmacytoma, and amyloid within the tumor is also rare.34 Although canine oral extramedullary plasmacytomas are rarely infiltrative, radiology, ultrasound, or computerized tomography is recommended for accurate clinical staging.

Cytology of an aspirate often allows a diagnosis of canine oral extramedullary plasmacytoma. Cytological features are typical for plasma cells and include eccentric round nuclei with a cartwheel appearance of chromatin, cytoplasmic vacuolation, and a perinuclear clearing. Multinucleate giant cells and large cells with bizarre nuclear shapes may also be visible and should not be confused with cells from a histiocytic neoplasm.

As described with skin tumors, canine extramedullary plasmacytomas histologically appear as round cells arranged in dense sheets or nests supported by a delicate lacy stroma. Cells have eccentric hyperchromatic nuclei and abundant, eosinophilic cytoplasm often with perinuclear clearing (Figure 13.11). Plasmacytomas have been subtyped using histological features, although no differences in biological behavior have been identified between subtypes. Diagnosis of a well‐differentiated oral plasmacytoma that contains lambda light chain amyloid is straightforward.35 However, plasmacytomas that contain marked anaplasia require differentiation from lymphoma, amelanotic melanoma, histiocytic tumors, and poorly differentiated sarcoma. Differentiation in these cases often requires IHC. Cells within a plasmacytoma should contain immunostaining for immunoglobulin light chains and the multiple myeloma 1/interferon regulatory factor 4 (MUM1/irf‐4). Melanomas, histiocytic neoplasms, and sarcomas do not contain MUM1 immunostaining. However, anti‐MUM1 antibodies do not allow differentiation between a plasmacytoma and a B‐cell lymphoma.31 To differentiate from oral lymphoma, B‐ and T‐cell immunostaining is recommended. Additionally, lymphoma is rarely confined to the oral cavity and the presence of multicentric involvement is more consistent with this diagnosis. Oral melanomas are expected to lack MUM1 immunostaining, but may show immunostaining to antibodies against Melan‐A, PNL‐2, and tyrosine reactive proteins 1 and 2. Neoplastic cells within the epithelium at the periphery of an oral melanoma are most likely to contain melanin pigment and exhibit diagnostic immunostaining. It should be noted that MUM1 immunostaining is rarely present in human melanocytic neoplasms.32 As discussed with tumors of the hematopoietic system, histiocytic proliferations are generally not confined to the oral cavity and are more common in specific breeds of dogs. Compared to a plasmacytoma, a higher proportion of cells within a histiocytic sarcoma are expected to be multinucleated and contain bizarre mitoses. Cells should demonstrate CD18 immunostaining and may also have erythrophagocytosis.

Micrograph of extramedullary plasmacytoma in a dog's mouth, illustrating round cells with hyperchromatic nuclei and amphophilic cytoplasm. Inset displays neoplastic cells with immunostaining.

Figure 13.11 Extramedullary plasmacytoma, mouth, dog. Round cells with eccentric hyperchromatic nuclei and abundant, eosinophilic amphophilic cytoplasm, often with perinuclear clearing, are arranged in sheets. Neoplastic cells show immunostaining for multiple myeloma 1/interferon regulatory factor 4 (MUM1/irf‐4; inset).

Complete surgical excision is the treatment of choice for plasmacytomas and is expected to be curative. However, complete excision of oral tumors can be difficult and recurrence was reported in 10% of dogs that had oral extramedullary plasmacytomas excised using aggressive surgical techniques.32 In a report of 4 dogs with oral extramedullary plasmacytomas that could not be excised, 2 dogs were euthanized due to the local effects of tumor growth and 2 dogs died of other causes. The 4 dogs had an MST of 90 days (range 37–830 days).32 Oral extramedullary plasmacytomas rarely metastasize and lymph node metastases were detected in just 1 of 32 dogs with this tumor.32

Mast cell tumor

Oral mast cell tumors are uncommon, representing 1.8 and 0.8% of oral cavity tumors in dogs and cats, respectively.13,14 Mast cell tumors within the oral cavity are extremely rare in horses and cattle.36

Clinical presentation is similar to other oral neoplasms. Mast cell tumors are generally soft and either sessile or exophytic. Diagnosis is straightforward from aspirates that contain predominantly mast cells. However, it can be difficult to differentiate between a mast cell tumor and an eosinophilic granuloma in aspirates that contain large numbers of eosinophils and macrophages accompanied by few mast cells. Microscopic identification of metachromatic granules by Giemsa or toluidine blue usually allows differentiation between mast cell tumors and other oral round cell neoplasms, but cytoplasmic granules may not be evident in Romanovsky‐stained cytological preparations. As oral mast cell tumors frequently metastasize (approximately 50% in dogs), cytological evaluation of multiple draining lymph nodes is important for accurate clinical staging.

In dogs, the mean age at diagnosis is 7.6 years (range 5–12 years) and mast cell tumors can involve the lips, buccal mucosa, gingiva, or tongue.37 In a study of 33 canine oral mast cell tumors, 18 had cytological evidence of lymph node metastasis at diagnosis.37 Distant metastases are also common and most dogs are euthanized due to morbidity caused both by recurrent local disease and distant metastases.37 In a series of 44 dogs with mast cell tumors of the oral cavity and perioral region of the muzzle, 21 dogs were euthanized due to the mast cell tumor with an MST of 52 months and a 1‐year survival rate of 68%.37 Survival time was not influenced by the location of the mast cell tumor, the treatment used, or the expression of chemokine receptor type 7 by the neoplastic cells. However, dogs that had identified lymph node metastasis at diagnosis had a shorter MST of 14 months.37

Few feline oral mast cell tumors have been reported. Cats are on average 7 years old at diagnosis (range 3–11.8 years) and tumors can be present at the mucocutaneous junction, in the soft palate, or in the buccal mucosa.13,14 A cat with an oral mast cell tumor that was suspected to have metastasized was successfully treated using chemotherapy.38


Oral lymphoma typically develops as part of more generalized disease and lymphoma is discussed in greater detail with tumors of the hemolymphatic system. In dogs, nontonsillar lymphoma comprises around 3% of oral tumors.39 Epitheliotrophic lymphoma of the lips, most frequently of T‐cell differentiation, is most common, although lesions are rarely confined to the oral cavity.40 Likewise it is extremely rare for a lymphoma of B‐cell origin to be confined to the oral cavity. Fourteen dogs with oral lymphoma of the lips (12 dogs), lips and tongue, and rostral intra‐mandibular space were treated by radiotherapy and had an MST of 770 days.40

Lymphoma is the fourth most common oral neoplasm of cats, but represents just 3% of oral neoplasia in this species.13 Affected cats have single or multiple gingival lesions that are often ulcerated and associated with secondary inflammation. Oral lymphoma has also been reported in horses, cattle, and goats.

Nerve sheath tumors

Nerve sheath tumors are a heterogeneous group of neoplasms and their diagnosis and classification is discussed with tumors of the skin. Oral nerve sheath tumors are rare; however, 4 of 29 canine41,42 and 4 of 59 feline43 nerve sheath tumors developed in the oral cavity. An oral nerve sheath tumor was reported in the maxilla of an older horse. Multiple perineurial proliferations that could not be unequivocally diagnosed as neoplastic have also been reported in the tongue of a horse. In general, recurrence of malignant oral nerve sheath tumors is common after surgical resection.


Oral liposarcomas are sporadically reported and appear to be most common within the canine tongue.19 Cytological differentiation between a liposarcoma and a granular cell tumor may be difficult as the cytoplasm of the neoplastic cells in a liposarcoma may appear granular rather than vacuolar.44 Histology using PAS staining should readily allow differentiation between a liposarcoma and a granular cell tumor.

Other mesenchymal tumors

Myxoma, myxosarcoma, myxofibrosarcoma, lipoma, hemangiopericytoma, histiocytic sarcoma, unclassified sarcoma, and osteosarcoma have been reported sporadically within the oral cavity of domestic animals.

Tumors arising from developmental abnormalities

Tumors of thyroid tissue displaced to the ventral pharynx during embryogenesis have been reported in dogs but are extremely rare. Mature to older dogs are primarily affected and the neoplasms can arise at the base of the tongue either from thyroglossal ducts or from remnants of the thyroid isthmus or central thyroid plate.42


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Melanocytic neoplasms

Oral melanocytic tumors are most common in dogs, although they are also regularly observed in cats. They are rare in horses, cattle, sheep, goats, and pigs.

Canine oral melanocytic tumors

General considerations

Melanocytic neoplasms are the most common malignant neoplasm in the oral cavity of dogs.1–7 Despite being so common, some can present a diagnostic challenge due to their poor pigmentation and cellular variability.6,8,9 In general, melanocytic neoplasms of the oral cavity are more aggressive and have shorter MSTs than cutaneous melanocytic neoplasms.8,9 Historically, all lip and oral melanocytic neoplasms were considered to be highly malignant. However, this dogma has recently been challenged with the identification of a subset of canine oral melanocytic tumors that have a more favorable prognosis.7,8,10,11 Although no canine oral melanocytic neoplasm should ever be unequivocally classified as benign, they can be subclassified as lowly or highly malignant melanomas. In one study, 8% of canine oral melanomas were classified as low malignancy and 92% as highly malignant. However, the true incidence of low malignancy neoplasms may be higher, as only 59% of the tumors classified as highly malignant subsequently recurred or metastasized after surgical excision.9 A study of 71 dogs with histologically well‐differentiated melanocytic neoplasms (melanocytic neoplasms of low malignant potential) located in the mucous membranes of the lips and oral cavity revealed that surgical excision resulted in an MST of approximately 3 years with some dogs surviving almost 4 years after diagnosis.10

Incidence and signalment

There is no sex or well‐established breed predisposition for the development of oral melanocytic neoplasms.12 However doberman pinschers and miniature and giant schnauzers have been suggested to have a higher incidence of oral melanocytic tumors and these tumors may be more likely to be of low malignancy.2 Other breeds that have been overrepresented in studies of oral melanocytic neoplasms include golden retrievers, Labrador retrievers, and cocker spaniels, although this may be due to a higher frequency of these breeds in the study population.12 Most melanocytic neoplasms occur in older dogs. Dogs with low malignancy oral melanomas are reported to have a mean age of approximately 8 years, whereas dogs with highly malignant oral melanomas have a mean age of approximately 12 years.1–4,7,12 The relative risk of developing oral melanocytic neoplasia increases with age more than with other oral malignancies. Dogs with oral melanocytic neoplasms are usually older than dogs that develop cutaneous melanomas.2,13

Canine oral melanocytic tumors most frequently develop on the gums and lips (Figure 13.12A).1,3,5,7,12 Occasionally, asymptomatic nodules less than 1 cm in size are found during dentistry. Many of these smaller lesions are pedunculated and are consistent with low malignancy tumors.10 Larger lesions (often 3–4 cm diameter) cause clinical signs of oral disease, are sessile, and often have an ulcerated surface (Figure 13.12B). Gingival tumors tend to be oval, molded by the anatomy of the jaw, and immobile. The surface may be black (Figure 13.12C), but white or pink mucosa can overlie pigmented tumors, and a red granulation tissue reaction secondary to ulceration may mask melanin pigment. The tumor consistency is firm unless necrosis and secondary infection have caused softening. Some tumors are uniformly black on cut surface, but more often there are foci with less pigment, and these areas are brown, gray, or white (amelanotic). Amelanotic neoplasms may give rise to pigmented secondaries and vice versa. The majority of oral melanocytic neoplasms grow as a sessile mass, but some may be pedunculated and grow from a relatively narrow stalk. Such pedunculated tumors tend to behave less aggressively although it is uncertain whether this is because of the biologic nature of the neoplasms or because they are easier to completely excise.

3 Photos of malignant melanoma in a dog's mouth displaying pigmented mass from the upper gum (a), ulcerated sessile pigmented mass on the hard palate (b), and an immobile mass on the inner lip (c).

Figure 13.12 Malignant melanoma, mouth, dog. (A) A lightly pigmented irregular mass is visible arising from the upper gum. (B) A sessile, ulcerated, variably pigmented mass is located on the hard palate invading caudally. (C) An oval, darkly pigmented, immobile mass is located on the inner lip.

(Images courtesy Douglas Thamm.)

Microscopic diagnosis

The identification of neoplastic cells containing melanin pigment will allow a cytological diagnosis of oral melanocytic neoplasm in many cases. However, due to the intratumor variation in neoplastic cell appearance, cytology should not be used to predict the behavior of an oral melanocytic neoplasm. Cytology of a poorly pigmented melanocytic tumor will often allow a diagnosis of a malignant neoplasm; however, additional histological studies are required for definitive diagnosis of a melanoma and more accurate prognostication. Aspiration of regional lymph nodes can be used to detect early metastatic spread. Approximately half of oral melanomas first metastasize to lymph nodes other than the mandibular lymph nodes and multiple nodes should be evaluated for nodal metastasis.14

There is currently some confusion regarding the use of terms used to describe melanocytic tumors in animals. In human pathology, melanocytic tumors have been extensively studied and the terminology has been well defined. Therefore, we propose that the terms used to describe the appearance and behavior of melanocytic neoplasms in domestic animal species should be equally well defined. In human pathology, a dermal melanocytic tumor is confined to the dermis with no epidermal involvement. A compound melanocytic tumor is defined as a benign melanocytic neoplasm with both epidermal and dermal components. In contrast to human medicine, the designation “compound” has been used in veterinary medicine for benign and malignant melanocytic tumors. Preferably, a malignant melanocytic neoplasm with both epidermal and dermal components should be described as an invasive melanoma. Dermal invasion is also often described as the vertical growth phase. In mucocutaneous melanomas the terms epithelial and submucosal or parenchymal are used instead of epidermal and dermal. Other features often described in oral melanocytic neoplasms include extension of the neoplastic cells to the dermo‐epidermal junction, junctional activity, lentiginous spread, and pagetoid growth. Extension of neoplastic cells to the dermo‐epidermal junction appears as the presence of neoplastic melanocytes within the superficial dermis, without these cells penetrating the basement membrane (Figure 13.13A). Junctional activity is defined as the presence of aggregates, nests or individual neoplastic melanocytes in the basal layer of the epidermis without a dermal component (Figure 13.13B). Previously junctional activity has been loosely used in descriptions of veterinary melanocytic tumors and we believe that the rigid application of the human definition of junctional activity will decrease confusion about this term in veterinary pathology. Lentiginous spread is defined as intraepidermal proliferation of migrating melanocytes which preferentially reside among basal keratinocytes. Theoretically, junctional activity may be differentiated from lentigenous spread by the cohesive nature of the neoplastic melanocytes preventing lateral spread. However, as migration cannot be assessed in histologic sections, both terms are often used interchangeably in human medicine, with lentiginous spread being used more commonly to clinically characterize a melanocytic neoplasm. Intraepidermal growth in melanomas is also often referred to as radial growth. Although junctional activity is a strong diagnostic criterion to differentiate melanocytic neoplasms from other tumor entities, it may be difficult to identify individual intraepidermal neoplastic melanocytes in H&E‐stained slides, especially if the neoplastic cells are not pigmented. Additionally, differentiation between hyperplastic and neoplastic intraepidermal melanocytes can be problematic. Features that indicate neoplasia include retraction artifacts around intraepithelial melanocytes as well as cellular atypia, especially variation in nuclear size, altered chromatin patterns, and nuclear pleomorphism. Lentiginous lateral spread is also an important feature to evaluate for prognostic purposes in order to accurately determine tumor margins, since it occurs away from the primary mass. Pagetoid spread is used in human melanocytic pathology to describe “upward spreading” of melanocytes into the epidermis; neoplastic melanocytes display pagetoid growth when they invade the upper epidermis from the stratum basale (Figure 13.13C). Although the term nevus was originally defined as a birthmark in humans, it has been used to describe benign melanocytic lesions in both human and veterinary pathology. Since this term lacks a good definition, it should be avoided when describing melanocytic neoplasms.

6 Micrographs of melanocytic tumors in dog's mouth with proliferating cells (a), junctional activity (b), pagetoid growth (c), oral melanocytic neoplasm (d), neoplastic cells (e), and compound melanoma (f).

Figure 13.13 Melanocytic tumors, mouth, dog. (A) Extension of proliferating melanin‐containing cells to the submucosal‐mucosal junction without penetration of the basement membrane is commonly observed. (B) Junctional activity is defined as the presence of neoplastic cells within the basal layer of the epithelium without submucosal involvement. These intraepithelial neoplastic cells are often well differentiated. Although these cells may not be recognized using routine stains, they can be the only neoplastic cells that are easily identifiable as melanocytes by IHC. Even if the submucosal component is negative with IHC, positive intraepithelial neoplastic cells are sufficient to diagnose melanoma (anti‐PNL‐2 antibody, Vector red chromogen, hematoxylin counterstain). (C) Pagetoid growth characterized by “upward spreading” of intraepithelial neoplastic melanocytic cells. There is also marked submucosal lymphoplasmacytic inflammation. (D) This canine oral melanocytic neoplasm of low malignant potential appears as a heavily pigmented, non‐ulcerated, small, raised, pedunculated nodule with the neoplastic cells in the mid and upper subepithelial parenchyma forming a symmetric, wedge‐shaped lesion with prominent fibrotic stroma. (E) The neoplastic cells in this low malignancy neoplasm are uniform in size with a round or ovoid nucleus that has a small, single, centrally placed nucleolus. There is little nuclear atypia and the mitotic count is low. (F) This highly malignant compound melanoma is characterized by deep nodular expansion into the underlying parenchyma and junctional activity as well as lentiginous (lateral) spread.

Canine oral melanocytic neoplasms of low malignant potential most closely resemble the common variant of blue nevi in people and have been described as histologically well‐differentiated melanocytic neoplasms.10,15 They tend to be heavily pigmented, non‐ulcerated, typically have a diameter of 1.0 cm or less, and are often raised or pedunculated (Figure 13.13D).10 Neoplastic cells are located in the mid and upper subepithelial parenchyma and commonly form symmetric, wedge‐shaped lesions with variably fibrotic stroma. Pigment granules may obscure the nucleus, requiring bleaching with 1% potassium permanganate. The neoplastic cells tend to be quite uniform in size and are round or elongated and contain a small round nucleus that often has a small, single, centrally placed nucleolus (Figure 13.13E).10 There is little nuclear atypia and the mitotic count is low, with less than 4 mitoses per 10 HPFs. Discrete intraepithelial nests of neoplastic melanocytes are often not visible in these neoplasms. However, junctional activity or lentiginous spread can be present in some melanocytic neoplasms of low malignant potential and may indicate an early stage of malignant transformation.

Highly malignant oral melanomas are most often compound (invasive) melanomas that are characterized by junctional activity and deep nodular expansion into the underlying parenchyma (Figure 13.13F). The intraepithelial component is believed to be the primary site of neoplastic cell proliferation and lentiginous growth is also responsible for lateral spread. This pattern closely resembles human mucocutaneous melanomas of the rectum or nasopharynx.6,7,15 Although these tumors appear grossly as well‐circumscribed solitary nodules, histology often reveals intraepithelial proliferation of discrete nests of often heavily pigmented neoplastic cells that may extend laterally for more than double the diameter of the grossly recognizable tumor. In invasive malignant melanomas, intraepithelial neoplastic cells are often better differentiated than the submucosal neoplastic melanocytes and may be the only cells that contain melanin pigment or show immunolabeling for Melan‐A or PNL‐2.8 Even with the submucosal component being negative for Melan‐A or PNL‐2, if the intraepithelial neoplastic cells are positive, then the diagnosis should still be melanoma. Due to the presence of these more differentiated, lentiginous spreading neoplastic cells, submitting surgical biopsy samples from the edge of lesions that include intact mucosal epithelium, rather than only an ulcerated surface over the center of a nodule, will increase the likelihood of differentiating a melanoma from a spindle cell sarcoma.8 Unlike the fairly uniform intraepithelial neoplastic cells, cells in the deeper portion of the tumors often show greater variation in the size and shape of both cytoplasm and nuclei. The deeper portion of the tumor is often divided into lobules, and the cells are supported by minimal collagenous stroma. Oral melanomas can be subdivided into subtypes using differences in cell morphology. The epithelioid or polygonal type consists of closely packed round or polyhedral cells with abundant cytoplasm, well‐defined borders, and large central nuclei with one or more prominent nucleoli (Figure 13.14A). In the spindloid or fibromatous type the nuclei are ovoid or elongate and have small nucleoli (Figure 13.14B). The third type is mixed and is characterized by both epithelioid and spindloid areas. A melanocytic neoplasm should be included in the list of differentials for any oral tumor with mixed epithelioid and spindloid features, regardless of the degree of pigmentation.

2 Micrographs of malignant melanoma in a dog's mouth featuring epithelioid type melanoma with polyhedral cells, borders, and nuclei (a) and spindloid type melanoma with spindle‐shaped cells (b).

Figure 13.14 Malignant melanoma, mouth, dog. (A) Epithelioid or polygonal type melanoma composed of closely packed round to polyhedral cells with abundant cytoplasm, well‐defined borders, and large central nuclei with one or more prominent nucleoli. Differentiating hyperplastic from neoplastic intraepithelial melanocytes can be challenging and requires close examination of cellular details. (B) Spindloid or fibromatous type melanoma composed of spindle‐shaped cells with ovoid or elongate nuclei that have small nucleoli. Melanomas without an epithelial component and scarce melanin pigment can be misdiagnosed as soft tissue sarcomas.

Additional rare types, such as whorled type (dendritic), balloon cell type, signet ring cell type, clear cell type and adenoid/papillary cell types have also been reported. Melanocytic neoplasms with osteocartilaginous differentiation occur rarely in the oral cavity and have to be differentiated from osteo‐ or chondrosarcomas (Figure 13.15A).16

3 Micrographs of malignant melanoma in a dog's mouth, with the antibody cocktail composed of PNL‐2, Melan‐A, TRP‐1, and TRP‐2 (a), cytoplasmic immunostaining (b), and cytoplasmic immunostaining for PNL‐2 (C).

Figure 13.15 Malignant melanoma, mouth, dog. (A) An antibody “cocktail” composed of PNL‐2, Melan‐A, TRP‐1, and TRP‐2 identifies the neoplastic cells as melanocytes. Note the presence of osteocartilagenous differentiation within the cells. (B) Strong cytoplasmic immunostaining for Melan‐A is highly specific for melanocytes. (C) Cytoplasmic immunostaining for PNL‐2 is also specific for melanocytes; however, identifying the cells as neoplastic requires evaluation of the cell morphology (all Vector red chromogen, hematoxylin counterstain).

Additional diagnostic tests

Pigmentation is an important diagnostic feature of oral melanocytic neoplasms and highly pigmented tumors are easily recognized grossly and microscopically. However, diagnosis of tumors with little or no pigment can be more problematic. Although histological features such as junctional activity or pagetoid spread support a diagnosis of a melanocytic neoplasm; ultimate confirmation requires identification of cells containing melanin in H&E‐stained slides or IHC.6–9 Antibodies that are highly specific for the diagnosis of oral melanocytic neoplasms include Melan‐A (Figure 13.15B), PNL‐2 (Figure 13.15C), and tyrosine reactive proteins 1 and 2. A “cocktail” containing all four antibodies provides the highest diagnostic sensitivity of canine melanocytic neoplasms.5,8,16–20 In contrast, antibodies against S100 and MITF‐1 are highly sensitive (almost all melanomas are positive) but have a low specificity (many other tumors are positive).5,8

Antibodies commonly used for the detection of human melanocytic lesions, such as HMB‐45 and tyrosinase, have a high specificity but very low sensitivity to detect canine oral melanocytic neoplasms.8 In contrast to melanocytic neoplasms, fibrosarcomas, histocytic sarcomas, peripheral nerve sheath tumors, and spindle cell SCCs do not contain immunostaining against Melan‐A, PNL‐2, or tyrosine reactive proteins, but, as described with the individual neoplasms, can be differentiated using antibodies such as CD34, laminin, CD18, or pancytokeratin. Melan‐A will also detect canine steroid‐producing tissues and their tumors such as adrenal cortical tumors and sex‐cord stromal tumors, but neither represents a histologic differential for oral melanocytic neoplasms. Masson Fontana silver stain has previously been used to highlight small quantities of melanin in poorly pigmented melanocytic neoplasms, but it is less specific and sensitive than IHC and will also react with lipofuscin and argentaffin granules. Electron microscopy has been used to identify premelanosomes in amelanotic tumors, but is rarely useful for routine diagnosis.

Prognostic indicators of canine oral melanomas

Canine oral melanocytic tumors can be tentatively subdivided into melanocytic neoplasms of low malignant potential and highly malignant melanomas by their gross and histological appearance. Melanocytic neoplasms of low malignant potential are less commonly ulcerated and tend to be small (55/71 melanocytic neoplasms of low malignant potential were <1.0 cm with only one tumor being >2 cm in one study10) and pedunculated. The degree of pigmentation of the neoplastic cells has been reported to be prognostic in human oral melanomas. However, using the pigmentation of canine oral melanocytic neoplasms to predict outcome has resulted in conflicting data.6,11,12,20,21 Overall, it appears that high pigment is an indicator of a good prognosis, but low or no pigmentation does not necessarily indicate a poor prognosis.6,10,11 Additionally, variability in the pigmentation of cells within different areas of the neoplasm makes it hard to assess the overall degree of pigmentation, especially if only a portion of the mass is evaluated.

A recent review of the literature revealed that nuclear atypia, mitotic count, and the Ki67 labeling index most consistently separated canine oral melanocytic neoplasms with low malignancy from those with high malignancy. In contrast, ulceration, inflammation, necrosis, or junctional activity did not consistently predict behavior.6,9,11

Nuclear atypia

Neoplastic melanocytes with little nuclear atypia contain a small nucleus with minimal clumping of chromatin.9,11 These cells tend to have a single, central nucleolus and potentially some condensed strands of nuclear chromatin extending from the nucleolus to the nuclear membrane with condensation along the inner surface of the membrane. Some cells may lack a nucleolus and have fine and evenly dispersed chromatin at the periphery of the nucleus.9,11 Compared to melanocytic neoplasms with low malignancy, highly malignant neoplasms contain cells with atypical nuclei characterized by large irregularly shaped nucleoli that are eccentrically located (Figure 13.16).9,11 They often have multiple nucleoli that, in some cases, are haphazardly connected to the inner surface of the nuclear membrane by thin strands of chromatin to give the appearance of a coarsely vacuolated nucleus.9,11 The use of nuclear atypia using a threshold value of ≥30% atypical nuclei per 100 cells evaluated predicted whether or not a dog would die of oral melanocytic tumor within 1 year in 86.3% of oral and lip melanocytic neoplasms with a sensitivity of 90.3% and a specificity of 84.4%.11 However, not all studies detected a correlation between nuclear atypia and outcome,13,16 possibly as the subjective nature of the measurement increases inter‐observer variation. Additional disadvantages to using nuclear atypia to predict prognosis include the long time required for assessment, the requirement of bleaching of pigmented tumors, and the inability to accurately assess the nuclear morphology of cells within spindloid tumors or other tumors with little nuclear detail.6,9,11

Micrograph of malignant melanoma in a dog's mouth illustrating the nuclei with irregularly-shaped multiple nucleoli, and featuring high mitotic index and scarce melanin pigment.

Figure 13.16 Malignant melanoma, mouth, dog. Note the atypical nuclei with large, irregularly shaped, often multiple nucleoli that are eccentrically located and haphazardly connected to the inner surface of the nuclear membrane. Numerous mitoses are visible. Melanin pigment is scarce.

Mitotic count

Assessment of mitotic count should be performed by determining the total number of mitotic figures in 10 consecutive HPF (total area 2.37 mm2), commencing in the area of highest mitotic activity.6,9,11 Around 80% of dogs with melanomas with ≥4 mitoses/10 HPF will live less than 1 year after diagnosis. In contrast, only 10% of dogs with neoplasms containing <4 mitoses/10 HPF will die within the first 12 months.6,9,11 In a study of 71 oral or lip melanocytic neoplasms of low malignant potential, 0 mitotic figures were seen in 56 tumors and the mitotic count in all tumors was <1/10 HPF.10 (See Appendix, p. 946.)

Mitotic count has traditionally been regarded as the easiest parameter to assess; however, some limitations must be recognized. These limitations apply to the assessment of mitotic activity in all neoplasms, but are particularly important in melanomas, as only small variations in the mitotic count influence prognosis. The first limitation is that it is critical that the area with the highest mitotic rate is used to determine the mitotic count. This can be difficult to determine, especially in large ulcerated neoplasms. Second, care has to be taken not to mistake apoptotic cells for those undergoing mitoses as nuclear morphology can be similar. It is recommended that only cells that are unquestionably undergoing mitosis are included in a mitotic count. Third, mitoses can be hard to identify in heavily pigmented areas or in spindloid tumors that often lack nuclear detail. Lastly, variations in the size of the field of vision between different microscopes may affect the mitotic count. This variation could be eliminated in future studies by standardizing the area counted (2.37 mm2) and how an area is selected, and defining mitotic figures (see Appendix, p. 944).

Ki67 immunolabeling

Ki67 is a marker of the growth fraction of neoplastic cells and more accurately predicts cell proliferation than a phase index such as mitotic index. Other advantages of Ki67 immunolabeling over the mitotic count include the easier assessment in heavily pigmented neoplasms (by using a red chromogen) and the prevention of mis‐identifying apoptotic and mitotic cells. In addition, it is easier to identify an area of the tumor with high Ki67 immunolabeling than an area with high mitoses. Furthermore, as measuring Ki67 immunolabeling is objective, it avoids the subjective assessment of determining the degree of nuclear atypia present within a neoplasm. Different studies have used different methods to measure Ki67 index, however, they all demonstrated the prognostic significance of Ki67 index for canine melanocytic neoplasms (Figure 13.17).11,13,16,22 In a study in which the average number of positively labeled neoplastic cell nuclei within 5 optical grid reticle 1 mm2 areas was determined at 40×, dogs with oral melanomas with a Ki67 index above the statistically ROC determined threshold value 19.5 had a significantly higher death rate within the first year after diagnosis than those with tumors below the threshold (p < 0.0005). The sensitivity and specificity of this threshold value was 87.1% and 85.7%, respectively.11

2 Micrographs of malignant melanoma in a dog's mouth illustrating few (a) and high (b) proportion of neoplastic cells with Ki67 immunostaining.

Figure 13.17 Malignant melanoma, mouth, dog. (A) Few neoplastic cells have nuclear Ki67 immunostaining in this low malignancy neoplasm. Positive labeling of nuclei in the stratum basale can serve as an internal control. (B) A high proportion of the neoplastic cells contain Ki67 immunostaining in this high malignancy neoplasm (both Vector red chromogen, hematoxylin counterstain).

Other prognostic indicators

Other methods to predict the behavior of a canine oral melanoma have been investigated. In a recent study, a decrease of expression of microRNA‐203 in canine oral melanocytic tumors was significantly associated with a shorter survival time.23 In contrast, expression of E‐cadherin, β‐catenin, KIT, p53, PTEN, Rb, p21, or p16 did not predict clinical behavior or survival in a series of canine oral melanocytic neoplasms.23–27


In humans, mutations in some genes (NRAS, BRAF, c‐Kit and G‐proteins of the Gαq family of GTPases) have been associated with distinct morphologic melanoma subtypes and a new classification of human melanocytic neoplasms based on epidemiological, clinical, histological, genetic, and biological aspects has been proposed.15,28 In contrast, little is known about the causative factors or the oncogenesis of canine oral melanocytic neoplasms. Mutations in exon 15 of BRAF or point mutations in KRAS2 and NRAS at the hot‐spot loci are either very rare or have not been detected in canine oral melanocytic neoplasms.29,30 Although many canine melanocytic neoplasms strongly express KIT, especially in their epithelial component, activating mutations in exon 11 of c‐Kit have not been discovered.27,31 Only a single nucleotide polymorphism was identified in a number of canine oral melanomas resulting in a silent mutation.31 The distribution of KIT‐positive neoplastic cells in canine oral melanomas is similar to that described for human mucosal melanomas.15,27,28 This expression pattern of KIT may explain the tendency for lateral spread due to an increased lateral mobility of the neoplastic melanocytes that is functionally driven by KIT pathway activation.15,28 In a recent study, ectopic expression of microRNA‐203 in melanoma cells reduced the levels of protein expression of the putative targets E2F3a, E2F3b, and ZBP‐89 and induced cell cycle arrest and senescence phenotypes, thereby suggesting an important role of microRNA‐203 as a tumor suppressor in canine oral malignant melanomas.32 Future classification of canine oral melanocytic neoplasms into biologically distinct subtypes based on morphologic and molecular characteristics is essential to develop targeted treatments and should be the goal of future studies.

Biological behavior

Highly malignant oral melanomas readily metastasize to regional lymph nodes (Figure 13.18) and at least two‐thirds to distant sites, the lung being most commonly affected. Lung metastases are often miliary, so they can be found at necropsy, but may not be detected in chest radiographs. The primary tumor grows rapidly and often invades underlying bone. Both local recurrence and metastases occur frequently following surgical resection. When attempting excision of an oral melanoma it is important to take both wide lateral and deep margins. Wide lateral margins are to ensure excision of grossly undetectable neoplastic cells spreading within the epithelium. Failure to achieve wide enough superficial margins may explain the high percentage of cases that recur at the excision site, despite complete excision of the main submucosal tumor mass. The presence of neoplastic cells in the epithelium of the lateral margins may be underappreciated if they are not immunolabeled with Melan‐A or PNL‐2.

Micrograph of malignant melanoma in a dog's mandibular lymph node displaying neoplasm metastases.

Figure 13.18 Malignant melanoma, mandibular lymph node, dog. Neoplasm metastases are visible.

The clinical stage may also be useful to predict the behavior of canine oral melanocytic neoplasms.1,4,12,33 Oral neoplasms are currently staged according to the scheme proposed by Owen (Table 13.1). One study reported significant differences in MSTs for dogs with surgically treated oral melanocytic neoplasms, with dogs surviving around 17, 5, and 3 months with stage I, II, and III disease, respectively.1 However, significant differences in MSTs between clinical stages have not been observed in all studies. One study reported significant differences in survival time when canine oral melanomas were classified using the size of the tumor, the location within the oral cavity, and the mitotic count within the neoplasm.12 Surprisingly, the presence of regional lymph node metastasis has not been found to influence remission length or survival times of dogs with oral melanocytic neoplasms.4,12 It is possible that this was due to the failure to detect nodal metastases that were present in some dogs and it is currently recommended that regional lymph nodes be removed and serially sectioned in people with malignant melanoma.34 Distant metastasis has been shown to be a significant negative determinant of survival,9 and the absence of detectable distant metastases at the time of surgery was statistically significant for longer remission lengths and survival times.12


Surgical excision is the current recommended treatment for canine oral malignant melanomas. Additional therapies such as radiation therapy or chemotherapy generally provide little clinical benefit. Most dogs that die due to oral melanomas die due to the effects of systemic metastasis.1,3 Therapies that are currently being assessed include xenogeneic DNA vaccines and the use of tyrosine kinase inhibitors.1,27,35,36 Compared to historically reported survival times, significantly longer survival times were reported in dogs that received a xenogeneic DNA vaccine that encoded for human tyrosinase.36 However, more than 50% of dogs that received the vaccine died of neoplasia prior to the end of the study.36 Overexpression of the tyrosinase transcript has been confirmed by RT‐PCR in a series of canine and equine melanocytic neoplasms.37 Although this expression forms the basis of a successful therapy, the actual protein tyrosinase was only detected in 3 of 49 formalin‐fixed canine oral malignant melanomas using IHC.8 Another study combined surgery with local suicide gene therapy using a subcutaneous vaccine composed of tumor cell extracts and xenogeneic cells producing human interleukin‐2 and granulocyte–macrophage colony‐stimulating factor. In this study, the combined treatment significantly increased the fraction of local disease‐free dogs from 13 to 81% and distant metastases‐free dogs from 32 to 84%.35 The efficacy of tyrosine kinase inhibitors in the treatment of canine melanocytic neoplasms remains unknown. However, although many canine melanocytic neoplasms strongly express KIT, especially in their lentiginous epithelial component, mutations in c‐Kit have not been discovered, suggesting that inhibition of tyrosine kinase may be effective in only a small proportion of tumors.27,31

Feline oral melanocytic tumors

Oral malignant melanomas are rare in cats and comprise less than 1% of oral malignancies in this species.38 No sex or breed predispositions have been reported and cats have been 8–16 (mean 12) years old.38,39 Tumor sites include gum, lip, palate, and tongue. The histological appearance generally resembles the combined epithelioid/spindloid (mixed) pattern seen in dogs and highly pigmented or pleomorphic tumors are uncommon.38 Neoplastic cells usually have large, vesicular nuclei with prominent nucleoli and few mitotic figures. In poorly pigmented tumors, the diagnosis is primarily based on junctional activity. Similar to dogs, most feline oral melanocytic neoplasms are expected to express PNL‐2 and Melan‐A.20 Some feline oral melanomas have been reported to express S100, although the specificity of this antibody is unknown.20 In one study, Ki67 index was shown to be a prognostic marker for feline melanocytic neoplasms; however, no oral tumors were included.22 Another study suggested that a high DNA index and high cellular aneuploidy could be predictive of malignant behavior.25 In general, prognosis is poor for feline oral melanocytic neoplasms. In one study, most cats were euthanized due to metastases in 1–135 days (mean 61 days).38 Cats with oral melanomas treated using radiation therapy had an MST of 146 days.39


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Non‐neoplastic oral tumors

Viral papillomas

Canine oral papillomatosis

Incidence, signalment, and etiology

As these lesions develop as a hyperplastic response to a viral infection and almost invariably spontaneously resolve, oral viral papillomas are best considered to be a hyperplastic disease rather than a true neoplasm. Canine oral papillomatosis is considered to be common; however, the true incidence is unknown as few dogs receive treatment and most cases are unrecorded. The disease is caused by canine papillomavirus (CPV)‐1 (formerly canine oral papillomavirus) and is mostly seen dogs that are less than 1‐year‐old. Aspects of the epidemiology of the disease are poorly understood with large numbers of CPV‐1 particles produced during clinical infection, but CPV‐1 DNA also detectable in swabs of clinically normal oral mucosa and haired skin.1,2 Outbreaks of disease have been reported in colonies of research dogs with up to 25% of dogs developing oral papillomas.2

Gross and microscopic diagnosis

Papillomaviruses increase both the division of infected basal cells and the commitment of basal cells to squamous maturation. This increases the number of cells within all layers of the epithelium resulting in epithelial thickening and folding and the formation of a papilloma.

Examination reveals exophytic lesions that are typically cauliflower‐shaped. They develop most frequently on the oral mucosa of the lips and pharynx, although they can also involve the tongue and esophagus. Most dogs will develop multiple papillomas and the presence of multiple large papillomas can result in bulging of the lips (Figure 13.19).

Photo of oral papillomatosis in a dog, displaying extensive papillomas with inset for micrograph of finely granular gray-blue cytoplasm.

Figure 13.19 Oral papillomatosis, dog. Despite the extensive papillomas, this dog showed no other clinical signs of disease. Cells within the superficial epithelium are enlarged by increased quantities of finely granular gray‐blue cytoplasm (inset).

Canine oral papillomatosis is usually diagnosed when multiple exophytic oral tumors are detected in a young dog. If confirmation of the clinical diagnosis is required, cytology may allow definitive diagnosis if well‐differentiated squamous cells that contain evidence of viral infection (smudged blue‐gray cytoplasm) are visible. However, such cells are infrequently present within aspirates and histology is often required.

Histologically, viral papillomas appear as polypoid lesions supported by a central fibrous stalk. Examination of the base of the papilloma reveals a sudden transition to hyperplastic epithelium covered by increased keratin. The surface of the papilloma is composed of many finger‐like projections of epithelium that are supported by a thin core of fibrous tissue. Replicating viral particles are assembled within the superficial layers of epidermis and virally induced cytopathologic changes may be visible in these cells. The most easily recognizable histological evidence of viral infection is the presence of cells containing increased quantities of finely granular gray‐blue cytoplasm. Cells containing a pyknotic nucleus that is surrounded by a clear halo (koilocytes or bird’s eye cells) may also be present. Intranuclear deeply eosinophilic viral inclusions tend to be rare and hard to detect. IHC detection of papillomaviruses is only possible when viral replication is present. Prominent lymphocytic inflammation without histological evidence of virally induced cell changes characterizes a regressing papilloma.

A viral papilloma can be differentiated from a nonviral squamous papilloma by the presence of virally induced cell changes or lymphocytic inflammation in the underlying dermis. Viral papillomas are strictly exophytic and any evidence of invasion of the basement membrane prompts a diagnosis of papillary SCC.

Biological behavior and prognosis

After infection by CPV‐1, there is an incubation period of 4–8 weeks before papilloma development. In most dogs, papillomas regress after 4–8 weeks and the dog is protected from further papilloma development.3 Although extensive papillomatosis can develop, dogs rarely show other clinical signs of disease and oral papillomatosis is a transient non‐life‐threatening disease for the overwhelming majority of dogs.

There are rare reports of dogs with persistent oral papillomatosis.4,5 This is presumed to be the result of a host immune dysfunction, although an underlying immunodeficiency is not always identifiable.4,5 Unless a normal host immune response can be restored, treatment of nonregressing oral papillomas is difficult and extensive involvement of the esophagus and haired skin can necessitate euthanasia.4 Vaccination against CPV‐1 prevents oral papillomatosis,6 but vaccines do not influence lesion resolution.4

Although an oral SCC has been reported to develop within an area of papillomatosis, there is no evidence that canine oral viral papillomas are predisposed to malignant transformation. CPV DNA can be detected in a small proportion of canine oral SCCs. However, as CPV‐1 DNA can also be detected in swabs of normal oral mucosa,1 it is difficult to prove a causative association.

Virally induced oral papillomas in other species

Oral papillomas in cattle usually develop caudally within the oral cavity as a component of bovine papillomavirus (BPV)‐4‐induced papillomatosis of the upper digestive tract. These are discussed with tumors of the esophagus. BPV‐12 appears to be a rare cause of oral papillomas in cattle.7 Extensive oral papillomatosis was observed in a 3‐year‐old dairy cow (Figure 13.20). Although a papillomaviral cause was suspected, no papillomavirus DNA could be amplified from the lesions.

Photo of oral papillomatosis in a cow displaying extensive exophytic papillomatous lesions involving the rostral mandibular gingiva and caudal maxillary and mandibular gingiva.

Figure 13.20 Oral papillomatosis, cow. Extensive exophytic papillomatous lesions are visible, involving the rostral mandibular gingiva and caudal maxillary and mandibular gingiva.

(Image courtesy of B.J. Mackintosh, VetSouth Ltd, New Zealand.)

Virally induced oral papillomas have been reported in domestic cats and are thought to be caused by Felis catus PV‐1.8 There are few reports of virally induced oral papillomas in other domestic species.

Feline eosinophilic granuloma complex

Location, gross appearance, and etiology

The feline eosinophilic granuloma complex (also referred to as feline eosinophilic dermatosis) is thought to be due to either a hypersensitivity reaction or dysregulation in eosinophil migration or function.9 Two manifestations of the feline eosinophilic granuloma complex can develop within the oral cavity. Feline indolent ulcers (also referred to as eosinophilic ulcers and rodent ulcers) most often develop at the mucocutaneous junction of the upper lip. Lesions appear as well‐demarcated areas of ulceration with an elevated margin, but without the formation of a mass. Ulcers can be up to 3 cm in diameter and result in lip distortion and exposure of the teeth. Unilateral lesions are most common, although bilateral and confluent lesions are reported. Feline oral eosinophilic granulomas (also referred to a feline collagenolytic granuloma) appear as solitary or multiple firm nodules that can affect the lingual, sublingual, tonsillar, or palate areas (Figure 13.21A). Ulceration, secondary infection, and necrosis is common within the lesions and, unlike indolent ulcers, oral eosinophilic granulomas are often painful and cause dysphagia.

Photo of eosinophilic granuloma in a cat's mouth displaying multiple ulcerated nodules (a) and micrograph illustrating eosinophilic debris from degranulated eosinophils (b).

Figure 13.21 Eosinophilic granuloma, mouth, cat. (A) Multiple ulcerated nodules are visible involving the tongue, gingiva, and tonsil. Squamous cell carcinoma was a differential. (B) Brightly eosinophilic debris from degranulated eosinophils centered on collagen fibers (flame figures) is visible within the submucosa. The cell debris is surrounded by large numbers of eosinophils with macrophages and occasional giant cells.

Microscopic diagnosis

Gross differentiation between a feline eosinophilic granuloma and an oral SCC is not possible and microscopic diagnosis is always recommended. The presence of numerous eosinophils on cytology strongly suggests a diagnosis of indolent ulcer (mucocutaneous junction) or eosinophilic granuloma. Histologically, both indolent ulcers and eosinophilic granulomas are characterized by eosinophils and eosinophil degranulation results in the presence of brightly eosinophilic cellular debris surrounding collagen fibers (flame figures) within the submucosa (Figure 13.21B). Flame figures are often surrounded by macrophages and giant cells with mast cells and smaller numbers of lymphocytes also present. Ulcerated lesions have prominent neutrophilic inflammation and superficial necrosis within the lesions. The presence of large numbers of eosinophils and macrophages usually allows differentiation from an oral mast cell tumor. Differentiation between an eosinophilic granuloma and an oral mast cell tumor is discussed with canine eosinophilic granulomas.

Canine eosinophilic granuloma

This rare disease is most commonly observed in younger Siberian huskies and cavalier King Charles spaniels, although has also been reported in other breeds and in mixed breed dogs.10 An inherited defect in normal eosinophil regulation is the suspected cause. Lesions appear as proliferative plaques or nodules that are most common on the lateral and ventral surfaces of the tongue and less common on the lips, hard palate, and soft palate.11 Ulceration and secondary infection is frequent and lingual lesions are generally painful.11 Other reported clinical signs of disease include halitosis, dysphagia, coughing during and after meals, and anorexia.10

Canine eosinophilic granulomas have a similar histological appearance to feline eosinophilic granulomas. Flame figures (eosinophilic cell debris surrounding collagen fibers) are prominent in lesions from Siberian huskies, but can be restricted to more superficial aspects of lesions in cavalier King Charles spaniels.10 Eosinophilic granulomas have some histological similarities with oral mast cell tumors. However, an eosinophilic granuloma will have a predominance of eosinophils with few normal‐appearing mast cells that are clustered around collagen fibers whereas a mast cell tumor will have both anaplastic mast cells and eosinophils diffusely present within the submucosa.


As oral neoplasia is rare in cattle, a mass in the oral cavity in this species is most likely to be inflammatory. Infection by Actinobacillus lignieresii is a common cause of stomatitis and glossitis in cattle and can result in nodular swelling and deformity (Figure 13.22). Although the tongue is most often affected (wooden tongue), poorly defined masses can be present anywhere from the lips to the forestomachs, and regional lymphadenopathy can be marked. Histology reveals characteristic pyogranulomatous inflammation with central colonies of coccobacilli surrounded by Splendore–Hoeppli material. This disease has also been rarely reported in other ruminants and pigs. Inflammatory oral tumors in production animals can also be due to infection by Actinomyces bovis, fungi, Nocardia sp., and Trueperella pyogenes.

Photo of actinobacillosis in a cow's mouth displaying marked granulomatous inflammation within the rostral gingiva resulting in tooth disruption and development of a protruding oral mass.

Figure 13.22 Actinobacillosis, mouth, cow. The presence of marked granulomatous inflammation within the rostral gingiva has resulted in tooth disruption and the development of a protruding oral mass.

(Image courtesy of B.J. Mackintosh, VetSouth Ltd, New Zealand.)

Canine hyperplastic gingival lesions

Both gingival hyperplasia and peripheral giant cell granulomas are discussed with odontogenic tumors.

Feline nasopharyngeal polyps

These develop most frequently in the mucosa of the nasopharynx, auditory tube, or middle ear of young cats. They are primarily a cause of respiratory tract disease; however, they rarely extend into the oropharynx and result in gastrointestinal signs such as dysphagia or anorexia.12 Histology reveals a fibrous core containing inflammatory cells covered by a mixture of respiratory and squamous epithelium.

Feline chronic gingivostomatitis

Feline chronic gingivostomatitis (FCGS) is a common and sometimes aggressive entity that can be as difficult to treat as some oral neoplasms. It encompasses all chronic non‐eosinophilic oral inflammatory diseases of cats, including the previously described diseases feline ulcerative stomatitis and glossitis, lymphocytic plasmacytic stomatitis, plasma cell gingivitis–pharyngitis, chronic faucitis, and chronic stomatitis. The use of FCGS as an umbrella term is currently preferred due to the considerable overlap between previously described diseases and the uncertainty of whether subdividing FCGS by location or histology provides information regarding the likely cause or progression of the disease.

FCGS is common and was diagnosed in 34 (0.7%) of 4858 feline consultations at first‐opinion veterinary hospitals.13 Cats with FCGS range from <1 to 20 years of age and no breed or sex predispositions have been reported.13 Both feline calicivirus and Pasteurella multocida subsp. multocida have been detected more frequently in cats with FCGS, although their role in this disease is unclear.14,15 There is little evidence that FCGS is caused by Bartonella sp., feline herpesvirus 1, FeLV, or FIV.

Lesions are often painful and cats show clinical signs of dysphagia, anorexia, weight loss, halitosis, and ptyalism. Examination reveals oral mucosa that is hyperemic, edematous, proliferative, and ulcerated, and osteolysis can be visible radiographically. Lesions are most common close to the junction between the oral cavity and the oropharynx and within rostral parts of the gingiva. The soft palate, oropharynx, tongue, and hard palate are less frequently affected.13 Lesions tend to be diffusely present within the oral cavity rather than appearing as a well‐defined mass. Epithelial hyperplasia is visible histologically with increased numbers of lymphocytes and plasma cells and variable numbers of macrophages and neutrophils.16 The lymphoplasmacytic inflammation often forms a prominent lichenoid band within the superficial submucosa. Ulcerated lesions contain necrosis and neutrophilic inflammation. Histology should allow definitive diagnosis with the detection of a mixed population of lymphocytes and plasma cells allowing differentiation from oral lymphoma.

Calcinosis circumscripta

This disease of dogs is defined by focal calcification within soft tissues. It is seen in young large breed dogs and German shepherds may be predisposed.17 Although generally considered to be idiopathic, trauma could predispose to calcification in some cases. These lesions most commonly involve the skin with only around 25% of calcinosis circumscripta lesions recognized in the oral cavity.17 The tongue is most frequently affected, although lesions have also been reported on the lip and gingiva.17 Lesions appear as well‐circumscribed domed nodules. Cytology reveals crystalline material and, with a supportive history and clinical presentation, can be diagnostic. If necessary, surgical excision and histological examination will allow definitive diagnosis. As discussed with skin tumors, lesions consist of central areas of mineral surrounded by granulomatous inflammation, multinucleate giant cells, and fibrosis. Other types of oral tumors rarely contain mineral and histological diagnosis is generally straightforward.


  1. 1. Lange, C.E., Zollinger, S., et al. (2011) Clinically healthy skin of dogs is a potential reservoir for canine papillomaviruses. J Clin Microbiol 49:707–709.
  2. 2. Nicholls, P.K. and Stanley, M.A. (1999) Canine papillomavirus‐A centenary review. J Comp Pathol 120:219–233.
  3. 3. Ghim, S., Newsome, J., et al. (2000) Spontaneously regressing oral papillomas induce systemic antibodies that neutralize canine oral papillomavirus. Exp Mol Pathol 68:147–151.
  4. 4. Nicholls, P.K., Klaunberg, B.A., et al. (1999) Naturally occurring, nonregressing canine oral papillomavirus infection: host immunity, virus characterization, and experimental infection. Virology 265:365–374.
  5. 5. Sundberg, J.P., Smith, E.K., et al. (1994) Involvement of canine oral papillomavirus in generalized oral and cutaneous verrucosis in a Chinese Shar Pei dog. Vet Pathol 31:183–187.
  6. 6. Bell, J.A., Sundberg, J.P., et al. (1994) A formalin‐inactivated vaccine protects against mucosal papillomavirus infection: a canine model. Pathobiology 62:194–198.
  7. 7. Zhu, W., Dong, J., et al. (2012) Characterization of novel bovine papillomavirus type 12 (BPV‐12) causing epithelial papilloma. Arch Virol 157:85–91.
  8. 8. Munday, J.S., Fairley, R.A., et al. (2015) Oral papillomas associated with Felis catus papillomavirus type 1 in 2 domestic cats. Vet Pathol 52:1187–1190.
  9. 9. Bloom, P.B. (2006) Canine and feline eosinophilic skin diseases. Vet Clin North Am Small Anim Pract 36:141–160.
  10. 10. Bredal, W.P., Gunnes, G., Vollset, I., and Ulstein, T.L. (1996) Oral eosinophilic granuloma in three cavalier King Charles spaniels. J Small Anim Pract 37:499–504.
  11. 11. Potter, K.A., Tucker, R.D., and Carpenter, J.L. (1980) Oral eosinophilic granuloma of Siberian Huskies. J Am Anim Hosp Assoc 16:595–600.
  12. 12. Byron, J.K., Shadwick, S.R., and Bennett, A.R. (2010) Megaesophagus in a 6‐month‐old cat secondary to a nasopharyngeal polyp. J Feline Med Surg 12:322–324.
  13. 13. Healey, K.A., Dawson, S., et al. (2007) Prevalence of feline chronic gingivo‐stomatitis in first opinion veterinary practice. J Feline Med Surg 9:373–381.
  14. 14. Dolieslager, S.M., Riggio, M.P., et al. (2011) Identification of bacteria associated with feline chronic gingivostomatitis using culture‐dependent and culture‐independent methods. Vet Microbiol 148:93–98.
  15. 15. Dowers, K.L., Hawley, J.R., et al. (2010) Association of Bartonella species, feline calicivirus, and feline herpesvirus 1 infection with gingivostomatitis in cats. J Feline Med Surg 12:314–321.
  16. 16. Harley R, Gruffydd‐Jones, T.J., and Day, M.J. (2011) Immunohistochemical characterization of oral mucosal lesions in cats with chronic gingivostomatitis. J Comp Pathol 144:239–250.
  17. 17. Tafti, A.K., Hanna, P., and Bourque, A.C. (2005) Calcinosis circumscripta in the dog: a retrospective pathological study. J Vet Med A Physiol Pathol Clin Med 52:13–17.

Tumors of the tongue

The most significant behavioral difference between lingual neoplasms and neoplasms elsewhere in the oral cavity is the less frequent invasion of bone by neoplasms of the tongue, increasing the chance of surgical excision. However, lingual neoplasms in dogs may have increased metastatic potential, with up to 40% of canine lingual SCCs reported to metastasize to regional lymph nodes compared to metastasis rates of just 15% for other oral SCCs.1,2 Human SCCs are well recognized to metastasize more quickly from the tongue than from other areas of the oral cavity, probably due to the high concentration of lymphatics within the tongue and the contraction of tongue muscles promoting the dissemination of neoplastic cells. In humans the prognosis of a lingual neoplasm is dependent on the likelihood of complete surgical excision, the location of the neoplasm in the tongue, and the presence of nodal metastases. Compared with neoplasms that develop at the base of the tongue, rostral SCCs in people have a more favorable prognosis due to more rapid detection, a greater chance of surgical cure, and, because there are fewer lymphatics in the rostral tongue, less frequent metastases.

Canine lingual neoplasia

Neoplasia of the tongue is rare in dogs, representing 3–6% of canine oral neoplasia.3,4 Around half of canine lingual neoplasms are detected as incidental findings prior to the development of clinical signs of neoplastic disease. When clinical symptoms are present, halitosis, ptyalism, oral hemorrhage, dysphagia, and anorexia are most frequently observed.5 Around 70% of canine lingual neoplasms are malignant. Although a wide variety of tumors can develop in the tongue, malignant melanomas (26%), SCC (24%), plasmacytoma (9%), granular cell tumor (7%), hemangiosarcoma (6%), fibrosarcoma (6%), nonviral squamous papilloma (4%), fibroma (4%), mast cell tumor (4%), lipoma, and lymphosarcoma (both 3%) were most common in a review of 793 reported lingual neoplasms.1,3–7 Granular cell tumors develop more commonly in the tongue than elsewhere in the oral cavity.

There is no region of the canine tongue that is predisposed to neoplasia development.1 The average age of dogs with malignant lingual neoplasia is 10 years and neoplasia develops more frequently in large than small breed dogs. Chow chows and Chinese shar‐pei dogs may be at increased risk of lingual melanocytic neoplasia.6

Three large studies have investigated factors that influence survival times of dogs with lingual neoplasms. These studies identified the presence of histologically clear margins after excision,2,5 a small neoplasm size,5,7 and the absence of metastases7 as being indicative of longer survival times. In contrast to studies of human lingual SCCs, neither a rostral location nor a low clinical stage was associated with a longer survival time.1 However, it should be noted that all three veterinary studies combined data from all types of malignant and benign lingual neoplasms in their analyses. As benign lingual neoplasms have longer survival times (>1607 days) than malignant neoplasms (286 days),5 the prognostic significance of each grouping was likely to be most dependent on the number of benign tumors in each group. As discussed with staging of oral tumors, when investigating prognostic factors it is essential that only one type of neoplasm is included in the analysis.

A study of 29 dogs with lingual malignant melanomas reported an MST of 241 days (range 4–1037 days). Metastases developed in 11 (38%) of the dogs and 9 (31%) of the lingual melanomas recurred after surgical excision.7 Eleven dogs with lingual malignant melanomas were reported to have an MST of 222 days (range 47–840 days) with distant metastases developing in 5 (45%) of the dogs.5

MSTs of dogs with lingual SCCs have been reported to be 216 days (range 31–865) in a study of 31 dogs7 and 301 days (range 204–496) in a study of 7 dogs.5 Metastatic disease developed in 6 (19%) of 31 dogs with SCCs with local recurrence observed in 10 (32%) dogs.7 Neoplasm recurrence was not observed in any of 5 dogs after excision of a lingual SCC with clear surgical margins, although one dog subsequently developed distant metastases.2,5 Lymph node metastases were detected at diagnosis in 1 of 10 dogs with lingual SCCs and an additional 3 dogs subsequently developed nodal metastases during treatment of the SCC.2 Nodal metastases were detected in 9 (43%) of a series of 21 dogs with lingual SCCs.1 Ten lingual SCCs were histologically subdivided into low, medium, and high grades, although whether this grading was significantly associated with prognosis was not reported.2

Evidence from a small number of cases of plasmacytoma and granular cell tumor indicate that these neoplasms have long survival times and a good prognosis. One of 5 plasmacytomas recurred after surgical excision; however, subsequent excision was curative. None of 4 granular cell tumors recurred after excision, despite 2 of the tumors showing histological evidence of incomplete excision.5

A study of 20 lingual hemangiosarcomas revealed a median overall survival of 553 days (range 60–2417). Survival times were significantly shorter in dogs that showed clinical signs of neoplasia at presentation (159 versus 633 days) and those with tumors greater than 2 cm in diameter (150 versus 633 days). Survival time was not associated with the completeness of excision, the location of the tumor, or the use of chemotherapy. Seventeen tumors were surgically excised. Of these, local recurrence was confirmed in 3 dogs, but suspected in an additional 4 dogs. Metastasis was confirmed in 3 dogs and suspected in an additional 6 cases.8

Lingual neoplasia in other species

The classification of feline oral SCCs is currently a little unclear, with some authors including SCCs that develop on the floor of the mouth close to the root of the tongue as lingual and others considering them as sublingual SCCs and a separate entity.9 When SCCs that develop close to the root of the tongue are excluded, lingual SCCs are reported to represent 4–11% of feline oral SCCs with some evidence that lingual SCCs develop in younger cats than gingival SCCs.9,10 While lingual SCCs should be easier to surgically excise and less likely to invade bone, there is currently no evidence that cats with lingual SCCs have different survival times to cats with SCCs elsewhere in the oral cavity. It is also unknown if lingual SCCs metastasize more rapidly than SCCs from other oral locations in cats. In addition to SCCs, melanoma, granular cell tumor, hemangioma, and hemangiosarcoma have also been reported in the tongue of cats.

Lingual neoplasia has rarely been reported in horses, with SCCs appearing to be the most common neoplasm at this location. Rhabdomyosarcomas are rare equine tumors. However, 4 of the 17 reported equine rhabdomyosarcomas developed in the tongue.11 One rhabdomyosarcoma was detected as an incidental finding during necropsy and 2 were successfully surgically resected. None were reported to metastasize. A chondrosarcoma was successfully excised from the tongue of a horse.12 There are few reports of lingual neoplasia in other domestic species.


  1. 1. Beck, E.R., Withrow, S.J., et al. (1986) Canine tongue tumors: A retrospective review of 57 cases. J Am Anim Hosp Assoc 22:525–532.
  2. 2. Carpenter, L.G., Withrow, S.J., et al. (1993) Squamous cell carcinoma of the tongue in 10 dogs. J Am Anim Hosp Assoc 29:19–24.
  3. 3. Todoroff, R.J. and Brodey, R.S. (1979) Oral and pharyngeal neoplasia in the dog: a retrospective survey of 361 cases. J Am Vet Med Assoc 175:567–571.
  4. 4. Vos, J.H. and van der Gaag, I. (1987) Canine and feline oral‐pharyngeal tumours. Zentralbl Veterinarmed A 34:420–427.
  5. 5. Syrcle, J.A., Bonczynski, J.J., Monette, S., and Bergman, P.J. (2008) Retrospective evaluation of lingual tumors in 42 dogs: 1999–2005. J Am Anim Hosp Assoc 44:308–319.
  6. 6. Dennis, M.M., Ehrhart, N., et al. (2006) Frequency of and risk factors associated with lingual lesions in dogs: 1,196 cases (1995–2004). J Am Vet Med Assoc 228:1533–1537.
  7. 7. Culp, W.T., Ehrhart, N., et al. (2013) Results of surgical excision and evaluation of factors associated with survival time in dogs with lingual neoplasia: 97 cases (1995–2008). J Am Vet Med Assoc 242:1392–1397.
  8. 8. Burton, J.H., Powers, B.E., and Biller, B.J. (2014) Clinical outcome in 20 cases of lingual hemangiosarcoma in dogs: 1996–2011. Vet Comp Oncol 12:198–204.
  9. 9. Martin, C.K., Tannehill‐Gregg, S.H., Wolfe, T.D., and Rosol, T.J. (2011) Bone‐invasive oral squamous cell carcinoma in cats: pathology and expression of parathyroid hormone‐related protein. Vet Pathol 48:302–312.
  10. 10. Hayes, A.M., Adams, V.J., Scase, T.J., and Murphy, S. (2007) Survival of 54 cats with oral squamous cell carcinoma in United Kingdom general practice. J Small Anim Pract 48:394–399.
  11. 11. Castleman, W.L., Toplon, D.E., et al. (2011) Rhabdomyosarcoma in 8 horses. Vet Pathol 48:1144–1150.
  12. 12. Wilson, G.J. and Anthony, N.D. (2007) Chondrosarcoma of the tongue of a horse. Aust Vet J 85:163–165.

Tumors of the tonsils

General considerations

The (palatine) tonsils are ovoid paired organs situated within the isthmus of the fauces at the junction between the oral cavity and oropharynx. The tonsils consist of localized aggregations of lymphoid tissue arranged in germinal centers. Stratified squamous epithelium covers and extends into the lymphoid tissue forming the tonsillar crypts. The crypts trap ingested or inhaled material allowing maximum antigen exposure. Histology normally reveals bacteria, keratinized cell debris, and inflammatory cells within the tonsillar crypts.

Tonsillar neoplasia can develop from the squamous epithelium, the lymphoid cells, or the supporting stromal cells. Neoplasms of the squamous epithelium are most common in the domestic species, with lymphoma second most common. Tonsillar lymphoma most frequently develops as a component of multicentric disease, although rare cases of localized primary tonsillar lymphoma have been reported in people.

Canine tonsillar squamous cell carcinomas

There are wide ranges in the reported incidence of these neoplasms varying from 3 to 46% of canine oral neoplasms.1 The study that reported the highest rate of tonsillar SCCs was of dogs living in a large English city in 1950. As lower rates of cancer were subsequently observed in later studies, it was hypothesized that exposure to air pollution was the cause of the high rate of tonsillar SCCs observed in the earlier study.1 However, rates of tonsillar SCCs were similar in large and small cities in a North American study2 and whether air pollution influences the development of canine tonsillar SCCs remains unknown. Dogs in large cities in some developing countries are currently being exposed to high levels of air pollution and it will be interesting to determine whether tonsillar SCCs are common in these dogs. Tonsillar SCCs are currently considered to be rare in dogs in North America, Europe, and Australasia.

The average age of dogs with tonsillar SCCs is 10 years and German shepherds may be predisposed.3,4 A quarter of canine tonsillar SCCs are first detected as an incidental finding.3 Clinical signs of tonsillar SCCs include coughing, lymphadenopathy, dyspnea, and dysphagia.3,5 Evidence of systemic disease such as anorexia and lethargy are infrequently observed at presentation.

Grossly, the majority of tumors appear as unilateral enlargement of the tonsil with protrusion of a firm gray mass from the tonsillar fossa. The tumor can have a papillomatous appearance and ulceration is common (Figure 13.23A). Invasion into surrounding structures is often detectable on gross examination. Bilateral involvement of the tonsils is reported in 7% of cases.3 Histologically, SCCs develop from crypt epithelium with infiltrative nests and trabeculae invading into the surrounding lymphoid tissue (Figure 13.23B). Tonsillar SCCs tend to be better differentiated than other oral cavity SCCs and cells around the periphery of the nests appear basiloid, but show maturation with cells close to the center of nests often containing prominent keratinization. Intercellular bridging is present and keratin “pearls” can be present. Tonsillar SCCs are usually ulcerated, resulting in secondary infection and neutrophilic inflammation. In tonsils that contain significant inflammation and necrosis, the presence of infiltrating dysplastic cells separate to areas of inflammation is critical to differentiate neoplasia from tonsillitis.

Photo of (a) squamous cell carcinoma in a dog's tonsil displaying neoplasm from the tonsillar fossa (arrowed) and (b) micrograph of neoplastic proliferation of tonsillar crypt epithelium with lymphoid tissue.

Figure 13.23 Squamous cell carcinoma, tonsil, dog. (A) The neoplasm appears as a firm mass protruding from the tonsillar fossa (arrow). (B) A neoplastic proliferation of tonsillar crypt epithelium is visible with residual lymphoid tissue on the right.

Canine tonsillar SCCs metastasize much more rapidly than other oral SCCs. Necropsy studies of dogs with tonsillar SCCs revealed regional lymph node metastases in 77–96% of dogs.5,6 Nine of 29 (31%) dogs also had metastases to the lung or liver.5 In a clinical study, nodal metastases were detected at diagnosis in 5 of 8 (63%) dogs with tonsillar SCCs, although metastases subsequently developed in the remaining 3 dogs during treatment.7 In another study, nodal metastases were detected by fine‐needle aspiration in 19 (59%) of 32 and lung metastases detected in 2 (5%) of 40 dogs with tonsillar SCCs.3 Nodal metastases can be accompanied by necrosis and suppurative inflammation and marked lymphadenopathy can be present despite the primary tonsillar SCC remaining small.5

Surgical excision, chemotherapy, and radiotherapy have all been used to treat canine tonsillar SCCs. Surgical excision as a sole therapy has been reported to result in survival times of 65–137 days. Survival times of 151–355 days were reported using a variety of multimodality treatments, although only 5 (11%) of 44 dogs remained alive 1 year after diagnosis.3,7,8 Few prognostic indicators have been established, but the presence of clinical signs of systemic disease at presentation was associated with a shorter survival time (MSTs of 103 days for dogs with anorexia and 22 days for dogs with lethargy) in one study.3 Despite the rapid metastasis of tonsillar SCCs, most dogs are euthanized due to pain and dysfunction caused by the primary neoplasm.3

Other canine tonsillar neoplasia

Canine tonsillar lymphoma develops as part of generalized lymphoma and bilateral tonsil enlargement is usually accompanied by widespread lymphadenopathy. Lymphoid hyperplasia can also result in tonsillar enlargement and has to be differentiated from lymphoma using cytology or histology. Rare tumors that have been reported in the canine tonsil include embryonic cysts and a lymphangiomatous polyp. Metastasis of oral malignant melanomas to the tonsils has also been reported.

Tonsillar neoplasia of other species

Tonsillar neoplasia represents around 2% of oral neoplasia in cats, with 1–3% of oral SCCs developing at this location (Figure 13.24).9,10 When buccal and tonsillar SCCs were considered to be one group, 4 cats with tonsillar and 1 cat with a buccal SCC survived longer (MST >724 days) after radiation and chemotherapy than 26 cats with other oral SCCs (MST 141 days).11 Whether feline tonsillar SCCs metastasize more rapidly than other oral SCCs is unknown as most cats with both oral and tonsillar SCCs are euthanized due to local disease prior to any metastases becoming clinically significant. Lymphoma of the feline tonsil is rare, comprising just 0.5% of oral neoplasia in this species.9 As in dogs, feline tonsillar lymphoma is usually part of generalized disease.

Photo of squamous cell carcinoma in a cat's tonsil displaying the neoplasm with infiltrated tissues surrounding the tonsil.

Figure 13.24 Squamous cell carcinoma, tonsil, cat. The neoplasm has infiltrated tissues surrounding the tonsil, making it hard to definitively confirm tonsillar origin from gross examination.

(Image courtesy of D. Aberdein, Massey University.)

There are no detailed reports of tonsillar SCCs in other domestic species. Tonsillar involvement as a component of multicentric lymphoma has been reported in cattle.


  1. 1. Bostock, D.E. and Curtis, R. (1984) Comparison of canine oropharyngeal malignancy in various geographical locations. Vet Rec 114:341–342.
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Odontogenic tumors and cysts

General considerations

Odontogenic tumors and cysts often present a diagnostic challenge. The anatomy of teeth and their genesis is complex. Numerous cell layers and tissue components are involved and interact in a tightly regulated fashion to form the normal tooth. The classification of odontogenic tumors is based on terminology applied to embryonal tissues of the developing tooth as well as the developed tooth. Therefore, a brief review of odontogenesis is provided below. Historically, there has been a lack of consistency in the classification of some odontogenic tumors. The present description aims to include more recently published observations, to achieve closer alignment with the human World Health Organization (WHO) classification, and to unify diverging opinions of a complex and sometimes confusing area of neoplastic disease in domestic animals.

Reports of metastasis of odontogenic tumors are limited to a single ameloblastic fibro‐odontosarcoma and as a group these neoplasms tend to be solitary and locally infiltrative, but not metastatic. Nonetheless, as there are significant behavioral and prognostic differences between individual odontogenic tumors a definitive diagnosis is essential. Additionally, it is critical to differentiate odontogenic tumors from other oral tumors that may have a less favorable prognosis, such as SCC, amelanotic melanoma, or fibrosarcoma. Odontogenic tumors can arise centrally (within the jaw bone) or peripherally (within the gingiva outside the bone). Identification of an odontogenic tumor is made by the presence of features of dental development or odontogenic epithelium. Odontogenic epithelium can be derived from the original enamel organ, the cell rests of Malassez or Serres, or from odontogenic epithelium in the gingival epithelium.

In tumors, odontogenic epithelium (Figure 13.25) is characterized by peripheral palisading of epithelial cells, location of the nucleus at the apical pole of the palisaded cell with a nuclear‐free zone along the basement membrane, basilar epithelial cytoplasmic clearing, and the connection of nonbasilar epithelial cells by long intercellular bridges reminiscent of the stellate reticulum (Box 13.1).

Micrograph of odontogenic epithelium, ameloblastic fibroma, having peripheral (basilar) cells (arrowed), with nonbasilar epithelial cells (arrowheads) connected by prominent intercellular bridges.

Figure 13.25 Odontogenic epithelium, ameloblastic fibroma. Odontogenic epithelium has peripheral (basilar) cells (arrows) that are palisaded and have nuclei located at the apical pole (away from basement membrane) producing a nuclear‐free zone along the basement membrane and cytoplasmic clearing. Nonbasilar epithelial cells (arrowheads) are connected by prominent intercellular bridges.

Ultrastructurally, peripheral (apical) displacement of nuclei in odontogenic epithelial cells is caused by accumulations of tonofilaments and secretory granules, but basal cytoplasmic clearing evident in sections of formalin‐fixed, paraffin‐embedded odontogenic epithelium is interpreted as an artifact of processing. Stellate reticulum is the loose meshwork of star‐shaped epithelial cells and their products that separate the inner and outer layer of the enamel epithelium during tooth development (Figure 13.26). Glycosaminoglycans produced by these cells attract water, leading to the typical wide intercellular spacing, loose appearance, and the lightly basophilic or amphophilic staining. The presence of stellate reticulum‐like tissue in tumors is generally easily recognizable and is consistent with an odontogenic origin. However, as not all odontogenic tumors contain stellate reticulum, the absence of stellate reticulum cannot be used to exclude an odontogenic neoplasm. Cells originating from the cranial neural crest form the ectomesenchymal (non‐epithelial) components of the developing and mature tooth. Odontogenic ectomesenchyme contributes to the formation of the collagenous periodontal ligament and tooth pulp, the dental hard tissues (cementum, dentin and enamel), and alveolar bone. Visualization of dental hard tissue such as cementum, dentin or enamel is helpful, but is an inconsistent finding. If present, these products have to be differentiated from osteoid or bone. This can be challenging, especially in the case of atypical poorly mineralized dentin, unless found immediately adjacent to odontogenic epithelium. The decisive features in naming odontogenic neoplasms are the amount and location of odontogenic epithelium and the presence or absence of ectomesenchyme (dentin, cementum, or enamel matrix and periodontal ligament‐like connective tissue). Odontogenic tumors are primarily seen in dogs and cats; they are rare in all other species.

3 Line drawings of tooth development displaying dental lamina growing into the subjacent tissue (a), dental bud shapes into the cap (b), and concurrent with changing shape to resemble a bell (c).
3 Micrographs of tooth development displaying concurrent with changing shape (d), odontoblasts from the ectomesenchyme of the dental papilla and deposit dentin (e), and enamel epithelium growing downward (f).
Line drawing of tooth development of Hertwig’s root sheath regressing, leaving behind epithelial rests of Malassez and cementoblasts covering root dentin with cementum.
Micrographs of osteoblasts and fibroblasts forming osseous dental alveoli and periodontal ligament (h), and collagen of the PDL anchors teeth to dental alveoli and antibodies to cytokeratin (i–k).

Figure 13.26

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Mar 30, 2020 | Posted by in INTERNAL MEDICINE | Comments Off on Tumors of the Alimentary Tract

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