JPC SYSTEMIC PATHOLOGY
Signalment (AFIP #2700698): Male German shepherd dog
HISTORY: Tissue from a male German shepherd dog, which had hematuria and a palpable mass in the posterior abdomen.
HISTOPATHOLOGIC DESCRIPTION: Urinary bladder: Arising from normal transitional epithelium, infiltrating lamina propria,forming multiple, exophytic papillary projections into the lumen, and occasionally cords of neoplastic cells in the submucosa, is an unencapsulated, poorly demarcated, poorly circumscribed densely cellular infiltrative neoplasm composed of polygonal epithelial cells arranged in cords and trabecula on a fine fibrovascular stroma. Neoplastic cells have distinct cell borders, moderate amount of eosinophilic granular cytoplasm, a round nucleus with vesiculate chromatin and one nucleolus. Anisocytosis is moderate and anisokaryosis is mild. The mitotic rate averages 3 per HPF. Multifocally, neoplastic cells have occasional large cytoplasmic vacuoles with eccentric nuclei (signet rings) or form pseudoacini containing eosinophilic homogeneous material, necrotic cellular debris, or lymphocytes and plasma cells. The lamina propria is expanded by increased clear space and dilated lymphatics (edema) and moderate numbers of lymphocytes, plasma cells, fewer macrophages and eosinophils.
MORPHOLOGIC DIAGNOSIS: Urinary bladder: Transitional cell carcinoma, papillary and infiltrating, German shepherd dog, canine.
CONDITION: Urothelial carcinoma, epidermoid carcinoma.
· Most commonly diagnosed tumor in the urinary bladder of domestic animals
· Urinary bladder neoplasia is common in dogs and cats, and rare in horses, sheep, goats, pigs and cattle except in endemic areas where bracken fern grows
· Higher prevalence in dogs that are older (9-11 years), female, neutered, obese, and of certain breeds (Airedales, beagles and Scottish terriers)
· Scottish terriers are 18% times more likely to get TCC, and exposure to lawns treated with herbicides and pesticides (specifically Phenoxy herbicides) further increases this likelihood
· Metastasis occurs late in the progression in 50-90% of cases; regional lymph nodes and lungs are common sites but peritoneal implantation and retrograde lymphatic spread to soft tissue and bone of the hind limbs is common
· There is significant correlation between tumor grade (differentiation) and invasion; tumor grade and metastasis/ depth of invasion; and desmoplastic response and metastasis
· The exact etiology is unknown, but the following have been associated with induction of transitional cell carcinomas:
o Intermediary metabolites of tryptophan (orthoaminophenol)
o Cyclophosphamide therapy
o Chemical carcinogens such as nitrofurans and formamide
o Viruses, chronic irritation and foreign bodies (sutures)
o Bracken fern
TYPICAL CLINICAL FINDINGS:
· Bladder cancers frequently produce painless hematuria
· Increased frequency, urgency, dysuria, and abdominal pain may also be present
· Nonspecific signs include weight loss, weakness, lameness, and dyspnea
TYPICAL GROSS FINDINGS:
· The trigone is the most common site, but any part of the bladder may be involved
· Most tumors are solitary and may cover a large portion of the bladder
· They may be papillary and project into the bladder lumen or they may be non-papillary, flat plaques with a broad base
· Tumors are occasionally not visible grossly despite diffuse infiltration
· Hydronephrosis may develop secondary to ureteral obstruction
TYPICAL LIGHT MICROSCOPIC FINDINGS:
· TCC are classified based on patterns of growth
· Papillary and infiltrating (most common) consists of papillary growths covered by multiple layers of neoplastic urothelium, infiltration of the tumor stalk, substantia propria, and muscle layers may occur; metastasis is expected with this type
· Papillary and noninfiltrating is similar without invasion of the stroma; metastasis is less likely
· Nonpapillary and infiltrating consists of flat nodules composed of neoplastic urothelium with marked cytological variation, this variant is most likely to metastasize
· Nonpapillary and noninfiltrating (carcinoma in situ) is least common and confined to the surface epithelium; cells can range from dysplastic to anaplastic; loss of cellular adhesion is a feature
· Neoplastic cells may be graded as well differentiated (grade I), moderately differentiated (grade II), or anaplastic (grade III)
· The degree of desmoplasia corresponds to metastatic potential
· Vascular invasion is evident in up to 40% of cases
· There may be areas of squamous or glandular metaplasia
· Adjacent urothelium is hyperplastic
ADDITIONAL DIAGNOSTIC TESTS:
· Immunohistochemistry: Uroplakin III is a specific and sensitive marker for canine transitional epithelial (urothelial) neoplasms, except for anaplastic tumors
· Urothelial carcinomas may also be positive for CK7, CK20, p63, HMWCK (CK1,5,10 and 14)
· Connexin 43 expression (membrane) in normal and dysplastic urothelium; reduced expression in carcinoma in situ; complete loss of expression with invasive carcinoma
· Antibodies directed against epitopes of Tumor-associated glycoprotein (TAG-72) (shown to be positive in 50% canine TCC)
· Expression of cyclooxygenase-2 in neoplastic urinary bladder epithelium, but not in normal epithelium, suggests this may be a useful marker for neoplastic transformation
Nonneoplastic bladder lesions:
· Polypoid cystitis - polypoid projections by proliferating connective tissue
· Follicular cystitis - numerous white nodules composed of aggregates of lymphocytes
· Brunn nests - invaginated nests of urothelial cells
Other urinary bladder neoplasms:
· Papillomas and adenomas are rare except in cattle grazing bracken fern
· Squamous cell carcinoma: Most common primary urinary bladder neoplasm in the horse
· Adenocarcinoma- arises from metaplastic transitional epithelium or urachal remnants
· Nonepithelial tumors/ Mesenchymal tumors:
o Leiomyoma/sarcoma – solitary or multiple, circumscribed, firm, pale white to tan masses in the urinary bladder wall
o Fibroma/sarcoma – arise from lamina propria connective tissue and project into the bladder lumen as solitary nodules
o Botryoid rhabdomyosarcomas – rare, but occur in young, large breed dogs especially Saint Bernards; they are botryoid masses that occur at the trigone and project into the urinary bladder lumen
· TCC is reported in most domestic and a few exotic species
· Cattle have increased incidence of transitional cell carcinoma associated with enzootic hematuria related to bracken fern (ptaquiloside) and/or bovine papilloma virus type 1 and type 2 (oncoprotein E5)
o Ptaquiloside toxin in bracken fern induces DNA alkylation; resulting in H-ras 1 mutation, which results in loss of control of the cell cycle
o E5 oncoprotein of papillomaviruses binds PDGFRβ (intrinsic tyrosine kinase receptor), which activates the MAP kinase, PI3 kinase and/or IP3 kinase pathway, which promotes production of growth factors (GF), GF receptors and controls the entry into the cell cycle; E5 can also activate c-Src, which induces cellular transformation independently of PDGF receptor activation
· Schistosoma haematobium infection in humans results in transitional cell carcinoma of the bladder
· Genital carcinoma of sea lions: in situ carcinoma caused by gamma herpesvirus (Otarine herpesvirus type 1); affected tissues include vagina, cervix, uterus, prepuce, urethra and penis
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