Urothelial carcinoma (“UC”, also called transitional cell carcinoma) is the most common type of urinary bladder cancer in dogs and humans. UC comprises ~2% of all cancer in both species, and causes >17,000 deaths in humans, and >40,000 deaths in dogs each year in the US. The majority of dogs with naturally-occurring UC have high grade invasive cancer that closely mimics muscle-invasive bladder cancer (MIBC) in humans. Although invasive UC can respond well to treatment, the cancer is lethal in approximately half of human patients, and in the majority of dogs. In addition to risk of urinary obstruction, invasive UC spreads to distant sites including lung, bones, and other sites in 50% of patients in both species. The canine model is serving an important role in testing and identifying new strategies for human trials. The very strong breed-associated risk, e.g. 20X higher risk in Scottish Terriers, enhances the value of the canine model in studying gene-environment risks.
Similarities in humans
Invasive UC in dogs closely resembles MIBC in humans in regards to: presenting symptoms / clinical signs, age at diagnosis, histopathologic and cellular features, molecular characteristics including signaling pathways and molecular subtypes, notable tumor heterogeneity, invasive and metastatic behavior, host immunocompetence, prognostic factors, and response to chemotherapy with platinum agents being most active in both species. Cyclooxygenase (COX)-2 is highly expressed in UC in both species, and COX inhibitors are commonly included in treatment protocols in dogs. EGFR and HER2 are also overexpressed in UC in both species and are being targeted for therapy. A recent advance has been the identification of luminal and basal molecular subtypes in canine UC that mimic those in humans. This is an important finding because cancer behavior, response to treatment, and prognosis are affected by the subtype of the cancer in humans, and thus it is important to replicate those subtypes in the animal model.
Differences in humans
Human UC consists of low grade superficial cancer in two-thirds, and high grade invasive cancer in one-third of patients. Most dogs have high grade invasive UC. The male:female ratio is 2:1 in humans, and 0.5:1 in dogs. This difference may be partially due to occupational exposures in men over a long latency period. Also, most dogs with UC have been spayed or neutered at an early age. UC typically occurs in the bladder trigone in dogs, but is more evenly spread across different area of the bladder in humans. In another difference, >80% of canine UC harbors a BRAFV595E mutation, the canine homologue of BRAFV600E mutation in human cancer. It is intriguing that this mutation drives 8% of all human cancer across cancer types, and is especially important in metastatic melanoma, but it is uncommon in human UC. It is interesting that although BRAF mutations are common in canine UC, the cancer still takes on the features of the luminal and basal molecular subtypes of human UC.
The most important risk factor for UC in humans is smoking, an important driver of the cancer in ~50% of cases. Exposure to aniline dyes, other chemicals, and cyclophosphamide also contribute to UC risk in humans. Key risk factors in dogs include exposure to older generation flea control products and lawn chemicals, along with obesity and female gender. Chronic inflammation and cyclophosphamide exposure are considered potential risk factors in both species. The strong breed-associated risk for UC in dogs includes a 20 fold increased risk in Scottish Terriers, and a 3-6 fold increased risk in West Highland White Terriers, Wirehair Fox Terriers, Shetland Sheepdogs and Beagles, compared to mixed breed dogs. Eskimo Dogs, Keeshonds, and Samoyeds have also been found to be at higher risk in some studies.
UC most commonly occurs in older individuals in both species. The most common presentation of UC in humans is unexplained hematuria in the absence of infection, stones, and other causes. The most common presenting clinical signs in dogs are hematuria, stranguria, increased frequency of urination, and inappropriate urination such as urinary accidents in the house. Distant metastases can be present in up to 20% of dogs at diagnosis. Although urinary signs predominate, rarely signs related to organ dysfunction due to metastases, or lameness associated with bone metastases or hypertrophic osteopathy can occur. UC can also be found incidentally during abdominal imaging performed to address other health concerns. The definitive diagnosis is made by histopathologic examination of tissues in both species.
Human MIBC is typically treated with cystectomy and neoadjuvant or adjuvant chemotherapy. Radiation therapy is used in “bladder sparing” protocols. Chemotherapy and immune checkpoint inhibitors are used to treat metastases. Up to 50% of patients appear cured, but recurrence and new primary tumors remain a concern. Invasive UC in dogs can be controlled for months to over a year, but is rarely curable. Cystectomy is rarely performed in dogs. Further study of radiation therapy will define possible benefits. Most dogs with UC are treated with COX inhibitors, chemotherapy, and combinations of these. COX inhibitors induce remission in 18-20% and stable disease in >50% of dogs, and greatly enhance the activity of chemotherapy. Chemotherapy agents such as cisplatin, carboplatin, gemcitabine, vinblastine, and mitoxantrone have response rates similar to those in human UC. Ureteral and urethral stents can be placed to physically relieve urinary obstruction.
Multiple groups are involved in research related to UC although options for case enrollment have been limited by the COVID-19 pandemic. The Purdue Comparative Oncology Program has a focused effort in canine and translational UC research, and operates a canine bladder cancer clinic at the Purdue University Veterinary Teaching Hospital. More information can be found at: https://www.purdue.edu/vet/pcop/index.php.
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