Diagnosis, treatment of transitional cell carcinoma (TCC) in dogs

Malignant tumors of the lower urinary tract include transitional cell carcinoma, squamous-cell carcinoma, adenocarcinoma, leiomyosarcoma, fibrosarcoma, hemangiosarcoma and rhabdomyosarcoma.

Transitional-cell carcinoma (TCC) is the most common of these malignancies and involves the bladder and/or the urethra. Affected dogs tend to be older and smaller in size (<10 kg). There may be a gender predilection, with females being more commonly affected, although this finding has not been consistent in all studies. Scottish Terriers, Shetland Sheepdogs, Collies, Airedales and Beagles are at a higher risk for developing these tumors.

Photo 1: Typical ultrasound appearance of TCC in the bladder.

Etiology

There appear to be both genetic and environmental risk factors for the development of TCC in dogs. In humans, cigarette smoking, exposure to chemicals, use of select medications and chronic inflammatory conditions of the bladder have been associated with an increased risk of bladder tumors.

Previous studies have found that dogs exposed to insecticidal dips, live near marshes or are overweight are at higher risk for the development of bladder tumors. Prior use of Cytoxan has been suggested as a risk factor. Two recent studies evaluated exposure to herbicides and topical flea and tick pesticides as possible risk factors in Scotties (Glickman 2004, Raghaven 2004). The conclusions were that the use of the topical flea and tick medications currently available did not increase the risk of TCC, but exposure to phenoxy herbicides did.

Although cause and effect can be proven, it still is prudent to recommend minimizing exposure to phenoxy herbicides. Interestingly, another study showed a decreased risk in development of bladder tumors in Scottish Terriers that consumed vegetables at least three times weekly; they had a 70 percent reduction in the risk of developing TCC (Raghaven 2005).

Photo 2: Typical ultrasound appearance of TCC in the bladder. This dog has a more diffuse thickening of the bladder than the dog in Photo 1.

Diagnosis

As would be expected, the most common clinical signs are stranguria, hematuria, dysuria and pollakiuria. Rarely is the presenting sign lameness, secondary either to hypertrophic osteopathy or bone metastasis. A tentative diagnosis can be made via identification of a bladder (Photos 1 and 2) or urethral mass (Photo 3) on ultrasound or other imaging, although other inflammatory and neoplastic diseases should be considered.

In male dogs, it can be difficult to determine if a mass in the prostate originates from the prostatic urethra or from the glandular tissue of the prostate. Male dogs that have been diagnosed with prostatic adenocarcinoma may actually have TCC of the prostatic urethra, which potentially carries a better prognosis (Photo 4).

Non-invasive diagnostics would include a urinalysis, urine culture, urine cytology and bladder tumor antigen testing. Cystocentesis should be avoided to prevent potential seeding of the tumor. Urine cytology can be helpful in making a diagnosis in up to 30 percent of dogs, although concurrent inflammation can make a definitive diagnosis of malignancy difficult. The commercially available bladder tumor antigen (BTA) test can support a diagnosis of TCC, although false-positive results can be obtained when there is significant proteinuria, glucosuria, pyuria or hematuria (Borjesson 1999). Given the potential for false-positive results, it is not recommended that the diagnosis be made strictly by a positive BTA test. False-negative results are less likely to occur, so this may be a more effective test for screening at- risk dogs for TCC.

Photo 3: A CT scan of urethral TCC. Arrows point to the urethra, which would not be visible on a CT scan in a normal dog.

It may be necessary to make a diagnosis using more invasive techniques, such as traumatic catheterization, cystoscopic biopsy or an open biopsy. The risks and benefits of a transabdominal aspirate of a bladder or urethral mass must be carefully considered for each patient, given the potential for abdominal seeding.

Treatment options

1. Surgery: Given the size and location of these tumors, surgical intervention often is not an option. Tumors in the apex are more amenable to surgical resection; however, there is still a high risk of local recurrence and/or distant metastasis so that surgery is not likely to be curative.

Photo 4: A CT scan of urethral TCC extending into the prostatic urethra. Arrows point to the enlarged prostate.

One-year survival times for patients with resectable tumors with surgery alone have been reported. The addition of adjuvant therapies such as piroxicam and/or mitoxantrone may improve survival beyond one year, but this has not been documented. Radical surgical procedures such as total cystectomy have been attempted but with poor outcome.

2. Drug options: One of the standard recommendations for dogs with TCC is the use of the NSAID piroxicam. In a pilot study, it was found that 20 percent of dogs with bladder tumors treated with piroxicam alone had a partial or complete response (Knapp 1994).

Survival times with piroxicam as a single agent are approximately six months. Other NSAIDs may have the same effect, though this has not been documented. The mechanism of action has not been proven, but it is suspected that piroxicam may have anti-angiogenic properties as well as direct cytotoxicity to neoplastic cells.

Even if there is no measurable response, many of the dogs have an improved quality of life due to the anti-inflammatory properties of piroxicam. The role of piroxicam and other NSAIDs as potential treatment options for other cancers is being studied.

Potential side effects of piroxicam include gastrointestinal ulceration and renal toxicity. For smaller dogs, it is recommended that the piroxicam be compounded into the appropriate dose size to reduce the risk of accidental overdose. Misoprostol and antacids can be used concurrently with piroxicam to prevent potential GI ulceration. It is recommended that renal function be monitored on a regular basis.

3. Chemotherapy: This option often is employed for the treatment of bladder tumors, either alone or in conjunction with piroxicam. The most commonly used drugs for canine TCC have been cisplatin, mitoxantrone, doxorubicin and carboplatin. Cisplatin appears to be the most effective drug as a single agent, although only partial responses have been reported. In one study, cisplatin was administered in conjunction with piroxicam but, given significant gastrointestinal and renal toxicity, this combination cannot be recommended. Despite the similarity of carboplatin to cisplatin, carboplatin does not appear to have activity against TCC.

As a single agent, mitoxantrone has been shown to have limited activity, but when used in combination with piroxicam has been shown to have more modest activity. When combined with piroxicam, the response rate is 35 percent with a median survival time of 12 months (Poirier 2004). Mitoxantrone is given intravenously once every three weeks. Potential side effects include gastrointestinal toxicity and myelosuppression, although serious side effects are rare. Mitoxantrone is available in generic form.

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A typical plan would be to administer one to two treatments of a given drug and then re-evaluate the tumor to check for a response. It can be difficult to evaluate responses objectively in the bladder, given that tumor size and shape are influenced by the volume of urine in the bladder. Ideally, the bladder should be filled with the same volume of saline prior to each ultrasound for an accurate comparison.

Treatment would be continued for those dogs that are considered responders. Stable disease can sometimes be considered a favorable response so that these patients may continue to be treated until there is evidence of progressive disease.

4. Photodynamic therapy: This option is being evaluated as a therapy for bladder tumors in dogs. Photodynamic therapy involves administration of a photosensitizing agent to the patient and then subsequent exposure of the tumor to a specific light wavelength from a light source.

One pilot study showed symptomatic relief in five dogs, ranging from four to 34 weeks. One advantage with photodynamic therapy is that re-treatment is possible without an increasing risk of side effects. One drawback is that there are only a handful of institutions that have the ability to provide this type of treatment.

5. Radiation therapy: Several studies have evaluated the role of radiation therapy in the treatment of bladder or urethral tumors, but have not led to increased survival times. Early studies involved the use of large doses of intra-operative radiation therapy.

Local recurrence was still problematic, and there were significant late effects, including bladder fibrosis and hydronephrosis secondary to ureteral fibrosis.

The use of multiple smaller doses of radiation therapy would potentially prevent these side effects; however, in studies where this was done, there did not appear to be any survival benefit.

6. Palliative options: Surgical placement of cystostomy catheters can be considered for those dogs that have urethral obstructions. Potential complications would include infection, urine leakage and the potential for accidental tube removal. A recent study evaluated the placement of urethral stents to manage urethral obstructions (Weiss 2006). Placement of the stents is minimally invasive and is done through the use of interventional radiology techniques.

The obstruction was relieved successfully in all 12 dogs, although survival times were short. Palliative radiation therapy, involving the use of several large doses of radiation therapy, may provide temporary relief of urethral obstruction, although expected response times may be two to four months at best.

Additional supportive care would involve the use of antibiotics for the treatment of concurrent urinary tract infections as well as pain management.

Prognosis

The long-term prognosis for dogs with TCC is considered to be guarded, but with treatment some patients can have a good quality of life for extended periods. Metastatic disease is present in 20 percent of dogs at the time of diagnosis. If dogs have a prolonged survival time, the metastatic rate can be as high as 50 percent to 60 percent.

Regional lymph nodes and lung are the most common sites for metastasis, but other locations such as bone have been reported.

The most important prognostic factor is the TNM Stage (T=primary tumor, N=regional lymph node, M=distant metastasis). As would be expected, dogs with invasive tumors and/or nodal and distant metastasis had shorter survival times.

Dr. Cronin earned her DVM degree from Cornell University in 1990. She completed an internship at the Animal Medical Center in New York and a medical oncology residency at North Carolina State University. She is a diplomate of the American College of Veterinary Internal Medicine in the specialty of oncology. After completing her residency, she was lecturer at the University of Pennsylvania Veterinary Teaching Hospital and a medical oncologist at Angell Memorial Animal Hospital in Boston. In 2001, she co-founded the New England Veterinary Oncology Group in Waltham, Mass.