JPC SYSTEMIC PATHOLOGY
DIGESTIVE SYSTEM
September 2021
D-N11

 

Signalment (JPC #4083908):  4-year-old Manx cat

 

HISTORY:  Right mandibular swelling

 

HISTOPATHOLOGIC DESCRIPTION:  Subcutis, right mandible:  Infiltrating and effacing the salivary gland, compressing the adjacent salivary gland duct, and elevating the fibrovascular capsule is a multilobulated, unencapsulated, infiltrative, densely cellular neoplasm composed of polygonal cells arranged in glands, islands, nests, and short cords on a dense fibrous to myxomatous or scirrhous stroma. Neoplastic cells have distinct cell borders and either have a moderate amount of brightly eosinophilic granular cytoplasm with few clear vacuoles and a round nucleus with finely stippled chromatin and 1-2 distinct nucleoli, or have an abundant amount of microvacuolated cytoplasm and a compressed, peripheralized nucleus (mucinous differentiation) with dense chromatin and indistinct nucleoli. Anisocytosis and anisokaryosis are moderate and there are 0-2 mitotic figures per 10 HPFs (2.37mm²). Glandular lumina often contain eosinophilic homogenous material (secretory product) admixed with erythrocytes, viable and degenerate neutrophils, and sloughed neoplastic cells.  Multifocally within the stroma, there are areas of cartilaginous metaplasia characterized by chondrocytes within lacunae, embedded in a pale amphophilic matrix.   At the margins of the neoplasm there are multifocal aggregates of perivascular lymphocytes and plasma cells, and small to moderate amounts of hemorrhage, fibrin, and edema with few hemosiderin-laden macrophages.  

 

MORPHOLOGIC DIAGNOSIS:  Subcutis, right mandible: Salivary adenocarcinoma, Manx, feline.

 

CONDITION:  Salivary adenocarcinoma

 

GENERAL DISCUSSION:

• All domestic animals have parotid, sublingual, and mandibular salivary glands.
  • Zygomatic glands (dorsal buccal glands) are not found in all animals; are present in dogs, cats, and ferrets
  • Neoplasia occurs most often in parotid and mandibular salivary glands
• Salivary glands contain lobules of adenomeres (which drain into intercalated ducts) consisting of mucous and/or serous cells surrounded by smaller numbers of myoepithelial cells
• Salivary gland adenocarcinoma, while rare in the salivary gland of humans, is the most commonly reported malignant salivary gland neoplasm in veterinary literature
• Cats tend to have more aggressive disease at the time of diagnosis and metastasis to regional nodes and distant sites (lungs) is more common; adenocarcinomas are the most common malignant salivary gland neoplasm in cats

 

TYPICAL CLINICAL FINDINGS:

• Development of a mass in the salivary gland region
• Halitosis, weight loss, anorexia, dysphagia, exophthalmos, Horner’s syndrome, sneezing, and dysphonia

 

TYPICAL GROSS FINDINGS:

• Usually unilateral
• Variable appearance based on type: from cystic with mucinous exudate to white, firm, and multilobulated

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Anaplastic epithelial cells arranged in ducts, acini, or solidly cellular areas
• Malignant epithelial salivary gland neoplasms are graded as low or high grade based on: mitotic rate, cellular pleomorphism, and glandular differentiation
  • In humans, grading predicts survival time, but this has not been proven in canine and feline adenocarcinomas
  • Loss of glandular differentiation is associated with a higher-grade and more aggressive neoplasm
• Contains no features of the other subtypes of malignant salivary gland epithelial tumors (see discussion in Differential Diagnosis section)

 

ADDITIONAL DIAGNOSTIC TESTS: 

• Mucus can be identified using mucicarmine, alcian blue, or PAS stains
• Cytology may allow for differentiation between neoplasia and inflammation (histology is required to distinguish malignant from benign neoplasia)

 

DIFFERENTIAL DIAGNOSIS:

• Benign epithelial salivary gland neoplasia:

• Salivary gland adenomas, four subtypes:

• Canalicular adenoma: tubules or anastomosing trabeculae of epithelial cells on a loose stroma
• Sebaceous gland adenomas: arise from sebaceous glands associated with salivary gland ducts, encapsulated with lobules of well-differentiated sebocytes surrounded by reserve cells (similar to cutaneous sebaceous gland adenomas)
• Ductal papillomas: proliferation of ductal epithelium with a core of connective tissue extending into the lumen of the duct (exophytic) or periductular connective tissue (inverted)
• Cystadenoma: multiple cysts containing mucin and papillary ingrowths of epithelial cells

• Benign mixed tumors (AKA pleomorphic adenoma): cells of epithelial and mesenchymal differentiation

• Neoplastic cells derived from myoepithelial or ductal reserve cells within the salivary gland.
• Epithelial cells form ducts or undergo squamous differentiation forming keratinized nests
• Mesenchymal cells surround epithelial cells or form solidly cellular sheets with a myxoid or hyaline ground substance; bone and cartilage is often present.

• Oncocytomas: large polygonal cells with bright eosinophilic granular cytoplasm

• Granules are PAS and PTAH positive, but toluidine blue negative (distinguishing them from mast cells)
• Can resemble rhabdomyomas; muscle specific IHCs are required for differentiation
• Ultrastructurally, granules represent mitochondria and make up approximately 60% of the cytoplasmic volume

• Other benign subtypes (4):

• Canalicular adenoma: tubules or anastomosing trabeculae of epithelial cells on a loose stroma
• Sebaceous gland adenomas: arise from sebaceous glands associated with salivary gland ducts, encapsulated with lobules of well-differentiated sebocytes surrounded by reserve cells (similar to cutaneous sebaceous gland adenomas)
• Ductal papillomas: proliferation of ductal epithelium with a core of connective tissue extending into the lumen of the duct (exophytic) or periductular connective tissue (inverted)
• Cystadenoma: multiple cysts containing mucin and papillary ingrowths of epithelial cells

• Other malignant salivary gland neoplasms:

• Acinic cell carcinoma: well-differentiated epithelial cells surrounded by a basement membrane arranged in small nests

• Epithelial cells may have many different appearances, e.g.:
• Resembling glandular acini with fine basophilic, PAS positive cytoplasmic granules
• Resembling intercalated ductal epithelium (small cuboidal cells)
• Large, vacuolated, clear cells with non-staining cytoplasm
• In general, these are low-grade malignancies with few mitoses and little cell anaplasia

• Mucoepidermal carcinoma: proliferations of squamous cells that differentiate into vacuolated mucus-secreting cells

• Squamous epithelial cells have distinct intercellular bridges but rarely produce keratin
• Mucus can be identified using mucicarmine, Alcian blue, or PAS stains
• Neoplastic cells are arranged in solid masses, trabeculae, or forming cystic spaces

• Malignant mixed tumors: composed of either malignant or benign epithelial and mesenchymal populations

• Most commonly appear as proliferation of anaplastic and invasive epithelial cells admixed with well-differentiated mesenchymal tissue that can form cartilaginous or osseous ground substance
• Can form de novo or within a pre-existing pleomorphic adenoma

• Other malignant subtypes (5):

• Cystadenocarcinoma: malignant epithelial neoplasm with a predominance of cysts; differentiated from cystadenoma by infiltrative growth pattern, higher mitotic rate, and cellular atypia
• Myoepithelial carcinoma: proliferation of spindle-shaped, plasmacytoid, or epithelioid cells in a solid or myxoid pattern
• Salivary gland SCC: rare; may be confused with invasive SCC from elsewhere in the oral cavity and squamous metaplasia of the salivary duct (in cases of salivary gland infarction)
• Basal cell adenocarcinomas: small, dark, basaloid cells arranged in nests with peripheral palisading
• Salivary duct carcinomas: intraductal cells that are invasive, forming papillary or solid masses with areas of central necrosis

• Other neoplasms that originate in the salivary gland: angiolipoma, fibrous histiocytoma, osteosarcoma, fibrosarcoma
• Metastatic neoplasms: lymphoma, SCC, fibrosarcoma, infiltrative lipoma, melanoma, mast cell tumor
• Non-neoplastic salivary gland lesions:
• Salivary gland cysts
  • Pseudocysts (AKA sialoceles): develop in the subcutaneous tissue due to rupture of a salivary gland duct
  • True salivary gland cyst: dilations of the salivary duct or gland
    • Often secondary to blockage of the duct
  • Salivary gland infarction (AKA necrotizing sialometaplasia, D-M12): coagulative necrosis of the salivary gland, possible thrombi of adjacent vessels, and marked dysplasia and squamous metaplasia of the salivary ducts adjacent to the areas of coagulative necrosis
  • Lipomatosis: slowly progressive unilateral enlargement of salivary glands by well-differentiated adipocytes, can occur secondary to inflammation of the salivary gland

 

COMPARATIVE PATHOLOGY:

Salivary gland neoplasia in other species:

• Reported in cattle, sheep, goats, horses, dogs, and cats; not pigs
• Dogs:
• Pleomorphic adenomas are the most common benign neoplasm
• Adenocarcinomas and acinic cell carcinoma are the most common malignant varieties
• A recent report of an oncocytic carcinoma in a miniature dachshund; diagnosis was based on numerous mitochondria ultrastructurally; most tumor cells were positive for cytokeratins AE1/AE3 and CAM5.2, E-cadherin, and mitochondrial ATPase beta subunit (ATPB) (Nakahira, J Vet Diagn Invest. 2017)
• An epithelial-myoepithelial carcinoma was identified in a dachshund with high grade transformation (Kishimoto, J Comp Pathol. 2015)
• Mice:
• Myoepithelioma (see D-N12) is the most common salivary gland neoplasm (submaxillary and parotid glands), commonly affected BALB/c females
• Myoepitheliomas also affect mammary, preputial, and Harderian glands
• Zoo/exotic/wildlife:
• Parotid basal cell adenocarcinoma recently reported in a big-eared opossum (Delgado, J Comp Pathol. 2018)
• Basal cell adenoma was reported in a black-tailed prairie dog that possibly reoccurred after resection into a basal cell adenocarcinoma (Ueda, J Comp Pathol. 2019

 

REFERENCES:

1. Delgado JB, Coimbra AAC, Santos-Cirqueira C, Sanches TC, et al. Parotid salivary gland basal cell adenocarcinoma in a big-eared opossum (Didelphis aurita). J Comp Pathol. 2018;159:21-25.
2. Gelberg HB. Alimentary system and the peritoneum, omentum, mesentery, and peritoneal cavity. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6^th St. Louis, MO: Elsevier; 2017:353.
3. Kishimoto TE, Yoshimura H, Saito N, Michishita M, et al. Salivary gland epithelial-myoepithelial carcinoma with high-grade transformation in a dog. J Comp Pathol. 2015; 153(2-3):111-115.
4. Munday JS, Lohr CV, Kiupel M. Tumors of the alimentary tract. In: Meuten DJ, ed. Tumors in Domestic Animals. 5^th Ames, IA: John Wiley & Sons; 2017:544-549.
5. Nakahira R, Michishita M, Kato M, et al. Oncocytic carcinoma of the salivary gland in a dog. J Vet Diagn Invest. 2017; 29(1):105-108.
6. Ueda K, Ueda A, Ozaki K. Basal cell adenoma of the salivary gland and possible recurrence as basal cell adenocarcinoma in a black-tailed prairie dog (Cynomys ludovicianus). J Comp Pathol. 2019; 168:13-17.
7. Uzal FA, Plattner BL, Hostetter JM. Alimentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer's Pathology of Domestic Animals. Vol 2. 6th ed. Philadelphia, PA: Saunders Elsevier; 2016:30.

 

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