The dog as an animal model for bladder and urethral urothelial carcinoma: Comparative epidemiology and histology

Abstract

Despite the recent approval of several novel agents for patients with metastatic urothelial carcinoma (UC), survival in this setting remains poor. As such, continued investigation into novel therapeutic options remains warranted. Pre-clinical development of novel treatments requires an animal model that accurately simulates the disease in humans. The aim of the present study was to evaluate the dog as an animal model for human UC. A total of 260 cases of spontaneous, untreated canine primary urethral and urinary bladder UC, were epidemiologically and histologically assessed and classified based on the current 2016 World Health Organization (WHO) tumor classification system. Canine data was compared with human data available from scientific literature. The mean age of dogs diagnosed with UC was 10.22 years (range, 4–15 years), which is equivalent to 60–70 human years. The results revealed a high association between UC diagnosis with the female sex [odds ratio (OR) 3.51; 95% confidence interval (CI) 2.57–4.79; P<0.001], surgical neutering (OR 4.57; 95% CI 1.87–11.12; P<0.001) and breed (OR 15.11 for Scottish terriers; 95% CI 8.99–25.41; P<0.001). Based on the 2016 WHO tumor (T), node and metastasis staging system, the primary tumors were characterized as T1 (38%), T2a (28%), T2b (13%) and T3 (22%). Non-papillary, flat subgross tumor growth was strongly associated with muscle invasion (OR 31.00; P<0.001). Irrespective of subgross growth pattern, all assessable tumors were invading beyond the basement membrane compatible with infiltrating UC. Conventional, not further classifiable infiltrating UC was the most common type of tumor (90%), followed by UC with divergent, squamous and/or glandular differentiation (6%). Seven out of the 260 (2.8%) cases were classified as non-urothelial based on their histological morphology. These cases included 5 (2%) squamous cell carcinomas, 1 (0.4%) adenocarcinoma and 1 (0.4%) neuroendocrine tumor. The 2 most striking common features of canine and human UC included high sex predilection and histological tumor appearance. The results support the suitability of the dog as an animal model for UC and confirm that dogs also spontaneously develop rare UC subtypes and bladder tumors, including plasmacytoid UC and neuroendocrine tumor, which are herein described for the first time in a non-experimental animal species.

Correlation of BRAF Variant V595E, Breed, Histological Grade and Cyclooxygenase-2 Expression in Canine Transitional Cell Carcinomas

“…Although canine and human TCC are largely and histopathologically very similar [45], there are some remarkable differences regarding the sex predisposition, histological grade, and prevalence of BRAF mutation, as well as a notable correlation of histological grade and intensity of COX-2 expression. A known sex predisposition for female dogs suffering from TCC [3] was confirmed by the present study.…”

Desexing Dogs: A Review of the Current Literature

“…Non-reproductive tumors with an increased risk across both sexes following desexing are cardiac and splenic hemangiosarcoma [112,117,[160][161][162], appendicular osteosarcoma [162][163][164][165], lymphoma [112,117,162,166], and transitional cell tumors of the bladder [167,168]. An increased risk for mast cell tumors has been described that may be specific to female dogs [120,162].…”

Pathological and clinicopathological features of canine and feline bladder disease

“…This finding was unique to the logistic regression model, highlighting the utility of this method in taking into account any interacting or confounding variables. Finding more males than females in the bladder neoplasia group is in contrast to the literature on UC in dogs, where females have up to three times higher risk than males (94,202), however the female to male ratio does level out in the high risk breeds (Shetland sheepdogs, West Highland white terriers and beagles) (203). The canine male to female ratio was comparable when evaluating all neoplasms together compared to evaluating UC alone.…”

“…Briefly, translational medicine is a branch of biomedicine that focuses on translating research findings in animals to improving human health (85). Traditional laboratory animals (rats, mice, rabbits) were used to research human diseases, however dogs and cats are being increasingly recognised as better models for human diseases as they share our environment and are exposed to similar stressors and external stimuli (94,174). In addition, compared to rodents the longer lifespan of dogs and cats allows the contraction of more age-related disorders, and also a longer time to explore disease progress and explore the safety and efficacy of novel therapies (174).…”