Oral Neoplasia

The nomenclature used to describe neoplastic or tumour-like gingival lesions (literally 'epulis') is determined by the composition of the tumour which may include odontogenic epithelium, odontogenic (dental pulp) mesenchyme or mesenchyme of periodontal ligament origin. Ameloblastoma is a rare, slow-growing, non-metastatic tumour of dogs and cats that arises from the odontogenic epithelium and generally involves bone (particularly the mandible) rather than the gingiva. These tumours may display prominent keratinization, in which case they are described as keratinizing ameloblastoma. The amyloid-producing odontogenic tumour is a similar lesion characterized by deposition of amyloid between the neoplastic epithelium. The most common of this group is the acanthomatous ameloblastoma (acanthomatous epulis), which presents in the dog as a cauliflower-like growth of the dental arcade which may infiltrate bone locally. This lesion also comprises odontogenic epithelium with surrounding mesenchyme of periodontal ligament origin. A second common canine lesion (and reported in cats) is the fibromatous epulis of periodontal ligament origin, which presents as a single mass (often relatively large) arising from the gingiva adjacent to a tooth. These lesions are rarely infiltrative and histologically comprise stroma characteristic of periodontal ligament with associated formation of collagen or osteoid and the presence of elongate epithelial cords that arise from the surface epithelium. The feline inductive odontogenic tumour is a rare lesion affecting the dental arcade of cats (particularly maxillary) that causes local osteolysis. These tumours are a mixture of odontogenic epithelium and odontogenic mesenchyme.

Squamous epithelial tumours are generally considered the most common oropharyngeal neoplasms in both species. Young dogs (mean age 1 y) may develop benign oral papillomata at numerous sites within the oral cavity and the lips. These lesions are virally induced and spontaneously regress with only very rare progression to malignancy. The tumours grow as exophytic, cauliflower-like masses comprising papillary folding of epithelium over narrow fibrovascular cores. Amphophilic intranuclear inclusions may be present in cells of the stratum granulosum that also display cytoplasmic ballooning degeneration and are termed 'koilocytes'. Virus particles may be demonstrated by EM and viral antigen identified by IHC. Canine oropharyngeal squamous cell carcinoma (SCC) may arise from the tonsillar epithelium or other sites (e.g., gingiva, lips, tongue, palate and pharynx). This is a tumour of older dogs (mean age 8 y) of any breed. Epidemiological studies have suggested a role for environmental pollution in the genesis of this tumour. SCC is locally infiltrative and almost invariably metastatic to local lymph nodes and often to more distant sites. The histological appearance is characteristic: infiltrating cords and nests of pleomorphic, mitotic, squamous epithelium with focal keratinization ('keratin pearls') within a scirrhous matrix. SCC is the most common oral neoplasm of the cat, most commonly arising in older animals (median age 11–12 y) from the tongue and gingiva. It is suggested that there may be geographical variation in presentation with, for example, more primary tonsillar lesions reported in the UK compared with the USA, and an association with environmental tobacco smoke is proposed.^1,2 Feline oral SCC is locally invasive but less commonly metastatic to regional lymph nodes than the canine disease.

Oral malignant melanoma is not uncommon in the dog but is very rare in cats. The average age of affected dogs is around 11 y. Breed predispositions are described (e.g., cocker spaniel, poodle, dachshund) but are controversial. The tumour most frequently arises from the gingiva or lip as an ulcerated nodular mass that may or may not be pigmented. Histologically the neoplastic melanocytes may be epithelioid, spindle, or mixed. They may be pigmented, with interspersed prominent melanophages, or amelanotic. The tumour cells may show epithelial 'junctional activity' and deep infiltration. IHC may be used to characterize amelanotic tumours, and the tumour cells will generally express vimentin, Melan A, NSE and S100. Most tumours metastasize to local lymph nodes and many to the lung, establishing miliary secondaries throughout the parenchyma. A proportion of canine oral melanocytic tumours are benign.³

Oral fibrosarcoma is the third most common oral tumour of the dog but is uncommon in the cat. Younger dogs may be affected, although a mean age of 7 y is reported. Large breeds may be more often affected, although there are no specific breed predispositions. The tumour more commonly arises from the gingiva than elsewhere in the oral cavity, and there is often local infiltration of underlying bone. Metastasis to local lymph nodes (20% of cases) and to lung (10–20% of cases) occurs. The histological appearance is of bundles of pleomorphic and mitotic spindle cells with occasional multinucleate cells.

Other, less common oral tumours include lymphoma (tonsillar or mucosal) in both species, which may be of either B- or T-cell (sometimes epitheliotropic) origin. Benign plasmacytoma presents as a solitary, non-infiltrative, non-metastatic lesion of the lip or gum of older dogs (mean age 10 y). These are composed of often highly pleomorphic plasmacytoid cells that are monoclonal on IHC (IgG or IgA), and there may be deposition of amyloid. Rare oral mast cell tumours are identified in both species (mostly arising from lip) and in the dog may be part of more widespread systemic disease.

Oesophageal Neoplasia

Oesophageal neoplasia is not common in dogs and cats, and of reported tumours, SCC is most frequent. Most affected animals are older (dogs 6–11 y, cats 10–12 y), and in both species the tumour most often arises in the mid-oesophagus. The tumour presents as an ulcerated plaque that becomes circumferential. The microscopic appearance is as described above with a marked inflammatory component related to ulceration. Oesophageal SCC is locally infiltrative (e.g., of trachea) and may metastasize to regional lymph nodes. It has been suggested that ingested carcinogens may play a role in the genesis of these lesions. Oesophageal adenocarcinoma, leiomyoma/sarcoma, and GIST (see below) are rare. In endemic areas, oesophageal sarcomata (fibrosarcoma, osteosarcoma) initiated by Spirocerca lupi infection may be common - particularly in stray animals. These lesions progress from a chronic inflammatory to neoplastic process.⁴

Gastric Neoplasia

Non-lymphoid gastric neoplasia is not uncommon in the dog but very rare in the cat. Adenocarcinoma is more frequent than adenoma, and the latter lesion may form a spectrum with benign adenomatous polyp. Canine gastric adenocarcinoma has a mean age at presentation of 7–10 y, and although not strong, breed predispositions have been suggested (Cairn terrier, West Highland white terrier, rough collie, Staffordshire bull terrier, Belgian shepherd). There is no clear aetiological ingested carcinogen and no evidence that Helicobacter plays a role in tumour induction. The tumours most often arise from the antrum or body and may appear as plaques, polypoid masses, or diffuse infiltrates. Mucosal ulceration is common, and gastric perforation with omental adhesion may occur. The most common histological appearance is of deeply infiltrative, tubular to acinar growth within a scirrhous matrix. Some tumour cells have extensive cytoplasmic vacuolation with the formation of 'mucin lakes' following rupture. In some tumours, vacuolated 'signet ring' cells containing mucin are prominent. In the absence of glandular differentiation, the tumour may be described as undifferentiated carcinoma, and IHC expression of cytokeratin, EMA, CEA, and CAM5.2 is to be expected. Canine gastric adenocarcinoma may spread to regional lymph nodes and seed the abdominal cavity but rarely metastasizes to other viscera or the lung.

Canine gastric leiomyoma and leiomyosarcoma are uncommon. Leiomyoma may remain undetected until late in life (mean age 16 y), but leiomyosarcoma is recognized earlier (mean age 7 y). The tumours arise most often from the gastro-oesophageal junction. The tumours appear amenable to surgical excision and are slow to metastasize.

Alimentary lymphoma may involve the stomach of dogs and cats, but primary gastric lymphoma is considered rare. Feline gastric lymphoma may be associated with Helicobacter infection, akin to human gastric MALT lymphoma.⁵ Gastric plasmacytoma is rare in the dog.

Intestinal Neoplasia

The most common benign transformation in the canine intestine is the recto-anal polyp (rectal papillary adenoma). These occur in middle-aged dogs (mean 7 y) without clear breed predisposition. The histological growth is papillary or tubular, and invasion of the submucosa is uncommon. There is some evidence that these lesions may progress to malignancy.

Both adenoma and adenocarcinoma may be more common in the canine colon than the small intestine. The mean age of onset for all canine intestinal epithelial neoplasia is around 9 y. Intestinal adenomas may be polypoid, whereas malignant variants are more likely to grow as plaques or by diffuse circumferential infiltration in an 'annular stenosing' fashion. The microscopic pattern of intestinal adenocarcinoma is as described above. These tumours are infiltrative and may extend to the serosa and mesentery and metastasize to local lymph nodes. Intra-abdominal seeding or distant vascular metastasis is rare.

Feline intestinal adenocarcinoma is more common than benign epithelial neoplasia. There is a suggested breed predisposition for the Siamese cat, and a mean age of 11 y is reported. There is no known association with retrovirus infection. These tumours most commonly arise in the jejunum or ileum and are rare in duodenum. The gross appearance is of an annular stenosing lesion, and the histological appearance is as described for the dog. Feline intestinal adenocarcinoma is metastatic to lymph nodes and may seed the abdominal cavity, leading to ascites.

Intestinal carcinoid is a rare tumour of the dog and cat that arises from neuroendocrine cells of the mucosa. The canine tumours are more frequent in the colon, rectum, and duodenum, whereas feline carcinoids are most often ileal in origin. In both species, the age range for these tumours is 9–13 y. The growth is either annular stenosing or nodular, and the histological appearance is of nests of cells with granular cytoplasm separated by connective tissue septae. On IHC these tumours express synaptophysin and chromogranin. The biological behaviour is for local infiltration (to mesentery), lymph node metastasis, and potential vascular metastasis to liver.

Relatively uncommon tumours of the intestine include haemangiosarcoma (cat) and fibrosarcoma (dog and cat).

Smooth muscle tumours are more common in the dog than the cat. Both leiomyoma and leiomyosarcoma are reported in dogs with an average age of 10 y. The site of origin of the tumours (collectively) is more frequently the jejunum and caecum than other intestinal sites. Feline leiomyoma and leiomyosarcoma are also more often small intestinal. The tumours are often nodular, involving the ante-mesenteric border. The histological distinction between benign and malignant tumours is difficult. On IHC these tumours express vimentin, desmin, muscle-specific actin (also found in skeletal muscle) and alpha-smooth muscle actin. Metastatic spread to lymph nodes and liver is a relatively uncommon occurrence. Another tumour within this spectrum is the gastrointestinal stromal tumour (GIST), which is histologically similar to the smooth muscle neoplasms but is thought to arise from the interstitial cells of Cajal (precursors to 'pacemaker cells' of the intestine). GIST may be distinguished by IHC expression of neurological markers (in some cases) such as S100, NSE, synaptophysin, or c-KIT.

Alimentary lymphoma (AL) is recognized in both the dog and cat. These tumours may be localized or involve multiple levels of the alimentary tract. They may be nodular, plaque-like, circumferential, or diffuse in growth. There is secondary involvement of mesenteric lymph nodes and abdominal viscera. IHC or determination of molecular clonality may be used to define the tumours as of T-cell (some epitheliotropic), B-cell or null-cell origin. A diagnostic algorithm for the differentiation between feline chronic intestinal inflammation and alimentary lymphoma is proposed, and the combination of light microscopy, immunohistochemistry, and clonality testing increases the sensitivity of diagnosis.⁶

AL is the most common feline intestinal neoplasm and the most common presentation of lymphoma in this species. Affected cats are generally older and have no evidence of retrovirus infection. There is a well-documented association with pre-existing lymphoplasmacytic inflammation, and the histological distinction between inflammatory bowel disease (IBD) and AL is a diagnostic challenge in the cat. The jejunum and ileo-caeco-colic junction are more commonly affected than duodenum, colon, and stomach. Three clinical variants are recognized with differing complete remission rates and survival times after treatment. Intermediate or high-grade alimentary lymphoma (IGAL/HGAL) is a focal T- or B-cell tumour; high-grade alimentary lymphoma (HGAL) is more often a diffuse T-cell tumour; and large granular lymphocyte lymphoma (LGLL) is a focal T-cell tumour.^7,8

AL is less common than multicentric lymphoma in the dog and is less common than intestinal epithelial neoplasia. The small intestine is involved more frequently than the large intestine or stomach. Although less often recognized than in the cat, an association with IBD is also proposed in some dogs. T-cell tumours predominate.

Other, less common intestinal round-cell tumours include plasmacytoma (dog), mast cell tumour (cat more than dog), and feline sclerosing alimentary mast cell tumour, characterized by marked fibrosis admixed with the neoplastic leukocytic infiltrate.

References

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

2.  Hayes AM, Adams VJ, Scase TJ, et al. Survival of 54 cats with oral squamous cell carcinoma in United Kingdom general practice. J Small Anim Pract. 2007;48:394–399.

3.  Spangler WL, Kass PH. The histologic and epidemiologic bases for prognostic considerations in canine melanocytic neoplasia. Vet Pathol. 2006;43:136–149.

4.  Dvir E, Clift SJ, Williams MC. Proposed histological progression of the Spirocerca lupi-induced oesophageal lesion in dogs. Vet Parasitol. 2010;168:71–77.

5.  Bridgeford EC, Marini RP, Feng Y, et al. Gastric Helicobacter species as a cause of feline gastric lymphoma: a viable hypothesis. Vet Immunol Immunopathol. 2008;123:106–113.

6.  Kiupel M, Smedley RC, Pfent C, et al. Diagnostic algorithm to differentiate lymphoma from inflammation in feline small intestinal biopsy samples. Vet Pathol. 2011;48:212–222.

7.  Moore PF, Rodriguez-Bertos A, Kass PH. Feline gastrointestinal lymphoma: mucosal architecture, immunophenotype, and molecular clonality. Vet Pathol. 2012;49:659–668.

8.  Barrs V, Beatty J. Feline alimentary lymphoma. 1. Classification, risk factors, clinical signs and non-invasive diagnostics. J Feline Med Surg. 2012;14:182–190.