Transitional cell carcinoma of the urinary bladder is by far the most common neoplasm of the urinary system in dogs. Less common histologic types of urinary system tumors include rhabdomyosarcoma, squamous cell carcinoma, adenocarcinoma, and various other mesenchymal tumors.1,2 Canine urinary system tumors most commonly occur in the bladder and proximal urethra; transitional cell carcinoma in dogs occurs most frequently at the bladder trigone. Consequently, transitional cell carcinoma may eventually lead to partial or complete obstruction of the urinary outflow as the tumor progresses. In male dogs, invasion into the prostate is common and is associated with a poorer prognosis.3
The aim of this review is to familiarize practitioners with the common clinical presentations of bladder transitional cell carcinoma in dogs as well as to describe current and future diagnostic tools and treatment options.
ETIOLOGY AND PATHOLOGIC CHARACTERISTICS
Several breeds, including Scottish terriers, Shetland sheepdogs, beagles, and West Highland white terriers, appear overrepresented for developing bladder transitional cell carcinoma. Of these breeds, Scottish terriers have the highest risk, with an approximately 19-fold increased odds ratio compared with mixed-breed dogs.3 But there is no known association between a dog's breed and the tumor's biologic behavior or response to therapy.
Female dogs are about twice as likely to develop bladder transitional cell carcinoma than are male dogs.1 One proposed reason for this gender disparity is that male dogs, in the process of territorial marking, urinate more frequently, which decreases the contact time of potential carcinogens with the urothelium.
Exposure to phenoxy herbicides has been linked to a significantly increased risk for the development of bladder transitional cell carcinoma in Scottish terriers.4 However, the newer topical insecticides such as fipronil and imidacloprid do not appear to elevate the risk of transitional cell carcinoma in this breed.5
The alkylating agent cyclophosphamide is known to increase the risk of bladder cancer ninefold in people and could play a similar role in dogs, although documented cases of transitional cell carcinoma developing in dogs after cyclophosphamide therapy for other malignancies are scarce.3,6,7
Additional risk factors for developing transitional cell carcinoma include obesity, possibly owing to adipose tissue serving as a storage area for carcinogens, and living near marshes sprayed with insecticides for mosquito control.8 Interestingly, no increased risk for developing transitional cell carcinoma was observed in dogs exposed to second-hand smoke in one study.8 But in people, a direct correlation exists between the number of cigarettes smoked daily and a higher risk for bladder transitional cell carcinoma.9
In dogs, bladder transitional cell carcinomas are typically locally infiltrative papillary carcinomas, and more than 95% have intermediate to high histologic grades; low-grade and in situ carcinomas are less common.2,3 Like most aggressive solid tumors, transitional cell carcinomas are highly vascular.10 The concentration of basic fibroblastic growth factor, a potent proangiogenic molecule expressed in many cancers,11 was recently found to be elevated in the urine of dogs with transitional cell carcinoma when compared with the urine of dogs with nonneoplastic lower urinary tract diseases, and these concentrations decreased in response to piroxicam therapy.12 This finding suggests a potential role for basic fibroblastic growth factor in the progression of canine transitional cell carcinoma and supports angiogenesis as a potential therapeutic target.
The inducible isoform of cyclooxygenase, COX-2, has generated a lot of interest in oncology in the last decade. Through its primary downstream metabolite prostaglandin E2 (PGE2), COX-2 can promote angiogenic factor recruitment, decrease immune surveillance, increase tumor growth and invasiveness, and reduce apoptosis.13 Overexpression of COX-2 has been demonstrated in numerous cancer types, including transitional cell carcinoma in dogs. In one study, COX-2 immunoreactivity was identified in all of 21 canine transitional cell carcinoma samples evaluated, but normal bladder epithelium did not demonstrate COX-2 immunoreactivity.14 It appears that COX-2 overexpression may play an important role in the development and progression of transitional cell carcinoma in dogs, and its inhibition is clearly a potential therapeutic target.
When canine bladder transitional cell carcinoma is suspected, an organized diagnostic approach can help to definitively diagnose it and may help to avoid seeding tumor cells to other locations.
Dogs with bladder transitional cell carcinoma typically present with signs consistent with lower urinary tract disease, including dysuria, hematuria, stranguria, and pollakiuria. The signs have often been present for weeks to months and may appear to wax and wane with temporary clinical response to empirical antibiotic therapy. Occasional presenting complaints may include pain or lameness from bone metastasis or paraneoplastic hypertrophic osteopathy.1
Physical examination may reveal a distended urinary bladder, and rectal examination may reveal thickening of the urethral mucosa and sublumbar or sacral lymphadenopathy. While the bladder mass can often be palpated transabdominally, physical examination may be unremarkable in many dogs with transitional cell carcinoma.
Initial diagnostic tests
In all older dogs with suspected lower urinary tract disease, perform initial diagnostic tests consisting of a complete blood count, a serum chemistry profile, urinalysis, and bacterial urine culture and antimicrobial sensitivity testing. Seeding of the tumor cells along the needle tract while performing cystocentesis has been reported, so, ideally, avoid this procedure if you suspect transitional cell carcinoma.17
Complete blood count and serum chemistry profile results are often normal in dogs with transitional cell carcinoma. Renal or post-renal azotemia may be present if the mass obstructs the ureters or urethra, possibly resulting in hydronephrosis and decreased renal function.
Urinalysis results are often suggestive of cystitis—with red blood cells, white blood cells, and bacteria present. Nonneoplastic, reactive transitional epithelial cells can appear similar to transitional cell carcinoma cells, so use caution when interpreting urine cytology results.
Bladder tumor antigen test
The recently developed bladder tumor antigen test (V-BTA—Polymedco) is a rapid latex agglutination assay used to detect tumor-associated glycoprotein complexes in the urine. Studies show the test to have high sensitivity for detecting transitional cell carcinoma. The specificity, however, is low. False positive results are frequently seen in dogs with nonneoplastic lower urinary tract disease such as infection, proteinuria, and glucosuria.18-20 The test may hold potential as a screening test, and dogs that have positive results should be further evaluated to rule out transitional cell carcinoma and potential nonneoplastic causes.
Histologic examination of biopsy samples
Histologic evaluation of bladder biopsy samples currently remains the only method to definitively diagnose transitional cell carcinoma. Tissue biopsy samples can be obtained by traumatic transurethral catheterization, cystoscopy, or surgical cystotomy. As previously mentioned for fine-needle aspiration of the bladder, avoid ultrasound-guided transabdominal Tru-Cut biopsies because of the risk of needle-tract seeding of tumor cells.
Contrast cystography or abdominal ultrasonography
Another advantage of ultrasonography is improved visualization of other abdominal structures. This includes better evaluation of the kidneys and ureters for possible complications and the assessment of potential metastatic sites, including the lymph nodes, liver, and spleen.
Once a diagnosis of transitional cell carcinoma has been confirmed, the patient should be clinically staged. Like most solid tumors, transitional cell carcinoma can metastasize to numerous sites, and suspect findings should be evaluated to obtain prognostic information before you pursue therapy (Table 1).3
On abdominal ultrasonographic examination, iliac (regional) and other abdominal (distant) lymph nodes are evaluated for lymphadenopathy or abnormal appearance. Although less common, metastasis can occasionally be identified in visceral organs, such as the liver or spleen. In addition, seeding from previous transabdominal needle-tract or transmural invasion of the bladder tumor can occasionally result in metastatic dissemination in the abdomen or carcinomatosis and is identified as free fluid, serosal thickening, or nodular lesions. Ultrasound-guided aspirates can be obtained for cytologic examination to confirm metastasis as needed.
The typical location of transitional cell carcinomas in dogs, the trigone, precludes complete surgical excision in nearly all cases. Additionally, multiple microscopic lesions are often present in the bladder. In people, this field carcinogenesis effect is well-documented, whereby multiple sites of the bladder mucosa undergo malignant transformation simultaneously or sequentially, subsequent to years of carcinogen exposure.24 As a result, therapy for transitional cell carcinoma can be frustrating.
In a retrospective study evaluating various therapies for bladder and urethral tumors, six of 10 dogs with apparent complete surgical resection of their urinary bladder transitional cell carcinoma experienced a local recurrence.1 Thus, surgery can be used as an emergency therapy to relieve a partial or complete obstruction but is generally only palliative, and owners should understand the high probability of recurrence or metastasis. Ideally, surgical excision of any malignant tumor should be planned with the intent of achieving 1- to 2-cm margins around the visible tumor borders. This is generally impossible in dogs with bladder transitional cell carcinoma.
A recent unpublished retrospective study found that surgical debulking resulted in a longer median survival time than diagnostic biopsy sampling (350 days vs. 207 days, respectively).25 Nevertheless, in the context of current medical therapy, the role of surgical debulking and its impact on the prognosis in dogs with bladder transitional cell carcinoma remain to be investigated.
Tumors located at the bladder's dorsal apex can be treated with partial cystectomy. Other surgical options include placing permanent cystostomy catheters (see "Palliative and supportive therapies") and performing urinary diversion procedures such as a complete cystectomy combined with ureterocolonic anastomosis. These surgical procedures have been used sporadically in veterinary patients, and while a few dogs demonstrated encouraging results, several others suffered considerable postoperative complications.26,27 Another interesting approach under evaluation to alleviate clinical signs in dogs with urethral or prostatic neoplasia leading to stricture is placing self-expanding metallic stents in the urethra.28
Two recent studies evaluated transurethral resection in dogs with marked urethral involvement. One study that evaluated the use of an electrocautery loop reported a significant risk of complications in female dogs with transitional cell carcinoma, including urethral perforation; male dogs with prostatic carcinoma benefited from this palliative approach.29 The other study used an electrovaporization technique with a rollerball electrode inserted via cystostomy in a small number of healthy dogs.30 This study group experienced a low complication rate and demonstrated the possible applicability of this technique in treating flat or small papillary bladder tumors.30 These minimally invasive surgical techniques warrant further investigation.
Systemic treatment of canine transitional cell carcinoma can include nonsteroidal anti-inflammatory drug (NSAID) monotherapy or a combination of chemotherapy and an NSAID.
The NSAID piroxicam, a nonselective COX inhibitor, has been evaluated as a single agent and in combination protocols for treating canine transitional cell carcinoma. In a prospective clinical trial, piroxicam monotherapy demonstrated an 18% overall objective response rate (6/34), including two complete responses; many patients achieved durable stable disease (minimal or no tumor progression for more than eight weeks).31 In addition, since moderate pain or discomfort often accompanies canine transitional cell carcinoma, piroxicam therapy tends to subjectively improve the quality of life and facilitate micturition in most patients, even in the absence of apparent measurable tumor response. The median survival time for the dogs in that study was 181 days.
Recent evidence suggests that COX-2 inhibition may not be the sole factor in the responses observed with piroxicam therapy and that transitional cell carcinoma may not depend on COX-2 for survival. Specifically, it was demonstrated that there is no association among tumor COX-2 expression, tumor PGE2 concentrations, and response to piroxicam therapy.32 Nevertheless, NSAIDs are a mainstay in treating canine transitional cell carcinoma, and ongoing studies are evaluating veterinary-approved NSAIDs as monotherapy as well as in combination with cytotoxic chemotherapy agents. The precise mechanisms by which NSAIDs exert their antitumor effects remain to be elucidated.
NSAIDs and chemotherapy
The standard-of-care medical therapy for canine transitional cell carcinoma generally combines systemic cytotoxic chemotherapy and the NSAID piroxicam.
Chemotherapy agents that have been studied include doxorubicin, cyclophosphamide, cisplatin, carboplatin, dactinomycin, and mitoxantrone.33-40 A study in 31 dogs compared three treatment groups: a doxorubicin and cyclophosphamide combination, surgery, and intravesical treatment with the alkylating agent thiotepa. There was a survival advantage for dogs treated with the doxorubicin and cyclophosphamide combination (median survival 259 days) compared with surgery (median survival 86 days) or intravesical thiotepa (median survival 57 days), but the small number of dogs in the study precludes firm conclusions or the routine use of a doxorubicin and cyclophosphamide combination to treat canine transitional cell carcinoma.41
Responses to monotherapy with the platinum agents cisplatin or carboplatin have been disappointing, with reported survival times of about six months.35,36 But when coadministered with piroxicam, carboplatin induced a higher response rate than when used alone, as determined by serial ultrasound measurements.36,42 However, the survival time was comparable to single-agent therapy with either drug, and the toxicities were considered unacceptable.42
Mitoxantrone, administered systemically or intravesically, has been extensively evaluated in treating invasive transitional cell carcinoma in people.43,44 In the veterinary literature, less information on mitoxantrone monotherapy for canine transitional cell carcinoma is available.40 Nevertheless, a combination of a platinum agent with either mitoxantrone or doxorubicin, as compared with single-agent platinum therapy, was identified as a positive prognostic variable in one study and led to a median survival time of 358 days.38 Furthermore, a multi-institutional study evaluated the coadministration of mitoxantrone and the NSAID piroxicam in 55 dogs with bladder transitional cell carcinoma. The results were an overall median survival time of 350 days—better than with either agent alone—with the combination being generally well-tolerated.39
General recommendations for systemic therapy
Because of evolving treatment options and recommendations for canine urinary bladder transitional cell carcinoma, consulting a veterinary oncologist is always recommended. When referral is not possible, consider offering palliative therapy with single-agent piroxicam (0.3 mg/kg/day orally with food). Also consider administering a combination of piroxicam and mitoxantrone (5 to 5.5 mg/m2 intravenously every 21 days; perform a complete blood count before each administration), currently regarded as standard-of-care therapy by many veterinary oncologists. Both therapeutic options carry high toxicity risks, including kidney (piroxicam), gastrointestinal tract (combination), and bone marrow toxicity (mitoxantrone), so closely monitor patients before and after instituting therapy.
A combination of a chemotherapeutic agent and NSAID other than mitoxantrone and piroxicam cannot be recommended and should be avoided until further studies demonstrate clear advantages with regard to safety and efficacy.
In a pilot study in 10 dogs with bladder transitional cell carcinoma that combined external beam radiation therapy with mitoxantrone chemotherapy and piroxicam, nine of the dogs experienced disease stabilization and improvement in clinical signs.45 However, the reported survival time of 326 days was comparable to piroxicam and mitoxantrone without radiation therapy. Nevertheless, in dogs with partial or complete obstruction of urinary outflow or dogs experiencing pain associated with the primary tumor or its metastases, radiation therapy is a viable therapeutic option.
Side effects associated with radiation therapy for transitional cell carcinoma are common and can mimic the clinical signs resulting from the tumor. Reported late side effects of radiation therapy, when administered as a single large intraoperative dose to the tumor and surrounding normal tissues, include hydroureter and hydronephrosis secondary to ureteral stenosis.46,47 Mild to moderate colitis is frequently reported as a late side effect of fractionated radiation therapy to the pelvis, and colonic perforation has been rarely reported.48
Given the absence of a clear benefit in terms of disease control or survival times when compared with standard medical management, radiation therapy should be reserved for select cases in which emergency intervention is necessary until additional studies indicate otherwise. Large fractions of megavoltage radiation therapy can help alleviate bone pain from skeletal metastases and are generally well-tolerated with no or minimal side effects.49
Palliative and supportive therapies
Pain management is essential and should focus on the primary tumor, metastatic sites, and hypertrophic osteopathy when present. Intravenous aminobisphosphonate (e.g. pamidronate) administration and palliative radiation therapy are good options for managing metastatic bone pain.52,53 The main mechanism by which bisphosphonates help alleviate bone pain in skeletal metastasis is by their antiosteoclastic activity.52 In our experience, antispasmodic drugs such as the benzodiazepines and phenoxybenzamine may benefit some patients with urethral or prostatic involvement. Renal failure is a potential complication in cases involving advanced local disease resulting in partial obstruction. Intravenous or subcutaneous fluid diuresis is essential to preserve renal function.
Several prognostic factors have been identified in dogs with transitional cell carcinoma. In a retrospective study of 102 dogs with confirmed transitional cell carcinoma, variables influencing outcome were identified by using the TNM staging system (Table 1).3 Specifically, it was shown that a higher T (primary tumor) stage at diagnosis was associated with an increased risk for developing nodal and distant metastasis, that a younger age was a risk factor for nodal metastasis being present at diagnosis, and that prostatic involvement was a risk factor for distant metastasis being present at diagnosis.3 In that same study, histologic evidence of vascular invasion and urethral involvement were associated with metastasis development after diagnosis.3 A strong correlation between a higher TNM stage at diagnosis and a shorter survival time was observed.
The overall prognosis in dogs with bladder transitional cell carcinoma is guarded. Superficial tumors at the bladder apex can occasionally be removed with margins by cystectomy, potentially leading to long-term survival. Nonetheless, owners should be warned that metastasis can occur and that new bladder lesions may arise after complete excision of a primary tumor. Dogs with nonresectable tumors, comprising most of the canine bladder transitional cell carcinoma patient population, have an unfavorable long-term prognosis, and most dogs will die of their disease, whether from complications from progressive local disease or from regional or distant metastasis. However, treating nonresectable transitional cell carcinoma with chemotherapy and an NSAID, along with palliative and supportive therapy as indicated, can be rewarding and provide a good quality of life for a median of six to 12 months.
FUTURE TREATMENT DIRECTIONS
Future promising therapies target specific dysregulated molecular pathways in transitional cell carcinoma. Research conducted in vitro with human bladder cancer cells revealed dysregulation of the epidermal growth factor signaling pathway.54 Selective inhibition of this pathway with the small molecule tyrosine kinase inhibitor gefitinib (Iressa—AstraZeneca) is a promising therapeutic avenue.54
Photodynamic therapy, which uses light-activated agents with relatively selective accumulation in tumor cells, also shows promise for treating transitional cell carcinoma, especially with superficial lesions. An in vitro study demonstrated the phototoxic effects of 5-aminolevulinic acid-based (ALA) photodynamic therapy on a canine transitional cell carcinoma cell line.55 This method is being evaluated in clinical trials in people, and preliminary results are encouraging.56
In people with high-grade superficial carcinoma in situ (superficial, not invading the basal layer), standard-of-care therapy involves intravesical bacille Calmette-Guérin, an attenuated strain of Mycobacterium bovis, acting as an immunostimulant.57 Intravesical therapy, with either chemotherapeutics or immunotherapeutics, is largely unexplored in veterinary oncology.39,58,59 While this may be due to the typically advanced local stage of disease in canine transitional cell carcinoma, it warrants further investigation.
Perhaps the most important prognostic impact will come in the form of early detection. Current research in people with transitional cell carcinoma focuses on several tumor markers, including the anti-apoptotic protein survivin. Survivin has been detected in 100% of people with new and recurrent bladder cancer and appears to be a reliable and sensitive marker for tumor detection.60 Survivin was recently evaluated as a potential prognostic variable in 15 dogs with transitional cell carcinoma. While the results were not statistically significant, a marked difference was observed in survival times for dogs with tumors expressing survivin (81 days) as compared with dogs with tumors that did not express it (226.5 days).61 Further investigation of this marker is necessary to clarify its utility in the prognosis and early diagnosis of canine transitional cell carcinoma.
Despite recent advances in therapeutic intervention, urinary bladder transitional cell carcinoma in dogs remains a frustrating disease for clinicians and owners. While improved quality of life and median survival times approaching one year are now reported, most patients with nonresectable primary tumors will eventually die as a result of inadequate local disease control.
David A. Heller, DVM
Louis-Philippe de Lorimier, DVM, DACVIM (oncology)
Timothy M. Fan, DVM, DACVIM (oncology, internal medicine)
Department of Veterinary Clinical Medicine
College of Veterinary Medicine
University of Illinois
Urbana, IL 61802
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