An update on diagnosing and treating urinary bladder transitional cell carcinoma in dogs

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.

In addition to molecular alterations in canine transitional cell carcinoma, muscle-invasive transitional cell carcinomas in people frequently carry mutations in the p53 and retinoblastoma tumor-suppressor genes.15 This aggressive form of the disease in people closely mimics transitional cell carcinoma in dogs, and these pathways are likely altered in canine transitional cell carcinoma. A recent unpublished study evaluating p53 protein expression demonstrated positive reactivity in four of seven canine transitional cell carcinoma cell lines and no reactivity in normal bladder mucosa.16 These findings are similar to the incidence of mutated p53 genes seen in transitional cell carcinoma in people, further strengthening the apparent similarities between transitional cell carcinomas in people and dogs and supporting canine transitional cell carcinoma as a good comparative model in clinical research (see the boxed text titled "Transitional cell carcinoma in people and cats: Is it similar to that in dogs?").

Transitional cell carcinoma in people and cats: Is it similar to that in dogs?

DIAGNOSIS

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.

Clinical signs

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

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

Bladder masses can be detected by contrast cystography or abdominal ultrasonography. Ultrasonography is more commonly used because it provides better visualization of the mass when proper equipment is used by an experienced ultrasonographer. To enhance visualization and localization of any masses (Figure 1), make sure the bladder is well-distended with urine or infused with saline solution.

Figure 1. An ultrasonogram of a mass in the trigonal area and a distended ureter resulting from partial ureteral obstruction in a 9-year-old male castrated Shetland sheepdog with transitional cell carcinoma.

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.

Additionally, ultrasound guidance can help you select an appropriate biopsy site for transurethral traumatic catheterization, improving the diagnostic yield. While this diagnostic procedure has a relatively high yield for biopsy samples, the samples are usually small, occasionally making histologic interpretation difficult.21 Samples obtained with transurethral traumatic catheterization can also be submitted for cytologic analysis and are often highly cellular and of good diagnostic quality when quickly processed and fixed on glass slides, leading to a presumptive diagnosis (Figure 2). Nevertheless, histologic examination of tissue biopsy samples remains the only definitive method of confirming urinary bladder transitional cell carcinoma.

Figure 2. A photomicrograph of a cytocentrifuged urine sample obtained by traumatic catheterization in a 10-year-old male castrated Scottish terrier showing sheets and clusters of round to polygonal cells with a moderate amount of basophilic cytoplasm. The nuclei are round with a stippled chromatin pattern and prominent, multiple nucleoli. Note the moderate anisocytosis and anisokaryosis (Wright's stain, 400X). (Photo courtesy of Dr. Anne Barger, DACVP.)

CLINICAL STAGING

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

Appropriate imaging includes three-view thoracic radiography and abdominal ultrasonography to evaluate for distant or regional metastatic disease, respectively. Reported metastatic rates in dogs with histologically confirmed transitional cell carcinoma are 20% to 37%, with regional (iliac) lymph nodes and lungs being the most common sites.1,3

Table 1 TNM Staging of Canine Bladder Transitional Cell Carcinoma*

The metastatic pattern of transitional cell carcinoma in the lungs can have a variety of radiographic appearances, including a nodular interstitial pattern, cavitated nodules, lobar interstitial or alveolar infiltrates, and multiple soft tissue nodules (Figure 3). Additionally, hilar lymphadenopathy may be present.22,23 Suspect lesions should ideally be interpreted by a board-certified veterinary radiologist.

Figure 3. A right lateral thoracic radiograph of a 10-year-old spayed female dalmatian with urethral transitional cell carcinoma and pulmonary metastasis in the form of soft tissue nodules evident at initial diagnosis.

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.

Obtain plain radiographs in patients with lameness, bone pain, or palpable bone masses (Figure 4). When available, bone scintigraphy can also help detect early bone metastasis since it has higher sensitivity than radiography in identifying the site of pathologic bone turnover (Figure 5).

Figure 4. A plain ventrodorsal thoracic radiograph of the left ninth, 10th, and 11th ribs of an 8-year-old female spayed Basset hound with bladder transitional cell carcinoma. A destructive, mixed lytic and proliferative lesion is visible in the 10th rib that was palpable on the chest wall. The results of a cytologic examination were compatible with carcinoma, and bone metastasis was confirmed. This dog also had widespread pulmonary metastasis.

TREATMENT

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.

Treatment options include surgical excision, systemic therapy, radiation therapy, and palliative and supportive therapies. Before initiating any form of therapy, clinically stage the tumor by using objective measurements. Base subsequent treatment decisions on the results of periodic restaging as well as on the patient's tolerance to the protocol.

Figure 5. Bone scintigraphy of a 10-year-old female spayed mixed-breed dog with bladder transitional cell carcinoma. This lateral bone scan image is of the right hindlimb and the pelvis, with cranial orientation to the right. Increased radiopharmaceutical uptake in the diaphyses of the tibia and metatarsal area (arrows) suggests bone metastasis (confirmed with radiography and cytology) while increased uptake in the stifle and coxofemoral joints (arrowheads) is compatible with degenerative joint disease.

Surgery

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 therapy

Systemic treatment of canine transitional cell carcinoma can include nonsteroidal anti-inflammatory drug (NSAID) monotherapy or a combination of chemotherapy and an NSAID.

NSAID monotherapy

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.

Radiation therapy

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

For dogs with nonresectable or recurrent local disease, as well as those with advanced metastatic disease, several palliative options may improve or restore their quality of life. For example, a cystostomy tube (Figure 6) can be surgically placed as a means of bypassing the trigone and urethra. Complications with this procedure are fairly common and include recurrent and, eventually, antibiotic-resistant lower urinary tract infections; urine leakage; and subcutaneous peristomal leakage and infection.26,50,51 Antibiotic therapy, based on bacterial culture and antimicrobial sensitivity testing, may need to be administered long-term.

Figure 6. A 9-year-old male castrated English springer spaniel with bladder transitional cell carcinoma. A cystostomy tube was placed, which improved the dog's quality of life. The dog lived an additional five months. The alopecia on the dogs right flank and thigh is a cosmetic side effect of previous external beam radiation therapy.

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.

PROGNOSIS

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.

CONCLUSION

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

REFERENCES

1. Norris AM, Laing EJ, Valli VE, et al. Canine bladder and urethral tumors: a retrospective study of 115 cases (1980-1985). J Vet Intern Med 1992;6:145-153.

2. Valli VE, Norris A, Jacobs RM, et al. Pathology of canine bladder and urethral cancer and correlation with tumour progression and survival. J Comp Pathol 1995;113:113-130.

3. Knapp DW, Glickman NW, DeNicola DB, et al. Naturally occurring canine transitional cell carcinoma of the urinary bladder. A relevant model of human invasive bladder cancer—a prospective study. Urol Oncol Semin Orig Invest 2000;5:47-59.

4. Glickman LT, Raghavan M, Knapp DW, et al. Herbicide exposure and the risk of transitional cell carcinoma of the urinary bladder in Scottish Terriers. J Am Vet Med Assoc 2004;224:1290-1297.

5. Raghavan M, Knapp DW, Dawson MH, et al. Topical flea and tick pesticides and the risk of transitional cell carcinoma of the urinary bladder in Scottish Terriers. J Am Vet Med Assoc 2004;225:389-394.

6. Johansson SL, Cohen SM. Epidemiology and etiology of bladder cancer. Semin Surg Oncol 1997;13:291-298.

7. Macy DW, Withrow SJ, Hoopes J. Transitional cell carcinoma of the bladder associated with cyclophosphamide administration. J Am Anim Hosp Assoc 1983;19:965-969.

8. Glickman LT, Shofer FS, McKee LJ, et al. Epidemiologic study of insecticide exposures, obesity, and risk of bladder cancer in household dogs. J Toxicol Environ Health 1989;28:407-414.

9. Hartge P, Silverman D, Hoover R, et al. Changing cigarette habits and bladder cancer risk: a case-control study. J Natl Cancer Inst 1987;78:1119-1125.

10. Inoue K, Kamada M, Slaton JW, et al. The prognostic value of angiogenesis and metastasis-related genes for progression of transitional cell carcinoma of the renal pelvis and ureter. Clin Cancer Res 2002;8:1863-1870.

11. Lutsenko SV, Kiselev SM, Severin SE. Molecular mechanisms of tumor angiogenesis. Biochemistry (Mosc) 2003;68:286-300.

12. Mohammed SI, Craig BA, Mutsaers AJ, et al. Effects of the cyclooxygenase inhibitor, piroxicam, in combination with chemotherapy on tumor response, apoptosis, and angiogenesis in a canine model of human invasive urinary bladder cancer. Mol Cancer Ther 2003;2:183-188.

13. Fosslien E. Molecular pathology of cyclooxygenase-2 in neoplasia. Ann Clin Lab Sci 2000;30:3-21.

14. Khan KN, Knapp DW, DeNicola DB, et al. Expression of cyclooxygenase-2 in transitional cell carcinoma of the urinary bladder in dogs. Am J Vet Res 2000;61:478-481.

15. Wu XR. Urothelial tumorigenesis: a tale of divergent pathways. Nat Rev Cancer 2005;5:713-725.

16. Greene SN, Purdue University, West Lafayette, Ind: Personal communication, April 2006.

17. Nyland TG, Wallack ST, Wisner ER. Needle-tract implantation following us-guided fine-needle aspiration biopsy of transitional cell carcinoma of the bladder, urethra, and prostate. Vet Radiol Ultrasound 2002;43:50-53.

18. Henry CJ, Tyler JW, McEntee MC, et al. Evaluation of a bladder tumor antigen test as a screening test for transitional cell carcinoma of the lower urinary tract in dogs. Am J Vet Res 2003;64:1017-1020.

19. Billet JP, Moore AH, Holt PE. Evaluation of a bladder tumor antigen test for the diagnosis of lower urinary tract malignancies in dogs. Am J Vet Res 2002;63:370-373.

20. Borjesson DL, Christopher MM, Ling GV. Detection of canine transitional cell carcinoma using a bladder tumor antigen urine dipstick test. Vet Clin Pathol 1999;28:33-38.

21. Lamb CR, Trower ND, Gregory SP. Ultrasound-guided catheter biopsy of the lower urinary tract: technique and results in 12 dogs. J Small Anim Pract 1996;37:413-416.

22. Mitten RW, Riedesel DH, Flatt RE. Cavitating pulmonary metastases in a dog. J Am Vet Med Assoc 1978;173:203-205.

23. Walter PA, Haynes JS, Feeney DA, et al. Radiographic appearance of pulmonary metastases from transitional cell carcinoma of the bladder and urethra of the dog. J Am Vet Med Assoc 1984;185:411-418.

24. Goto K, Konomoto T, Hayashi K, et al. p53 mutations in multiple urothelial carcinomas: a molecular analysis of the development of multiple carcinomas. Mod Pathol 1997;10:428-437.

25. Knapp DW, Purdue University, West Lafayette, Ind: Personal communication, April 2006.

26. Cornell KK. Cystotomy, partial cystectomy, and tube cystostomy. Clin Tech Small Anim Pract 2000;15:11-16.

27. Stone EA, Withrow SJ, Page RL, et al. Ureterocolonic anastomosis in ten dogs with transitional cell carcinoma. Vet Surg 1988;17:147-153.

28. Ko GY, Kim GC, Seo TS, et al. Covered, retrievable, expandable urethral nitinol stent: feasibility study in dogs. Radiology 2002;223:83-90.

29. Liptak JM, Brutscher SP, Monnet E, et al. Transurethral resection in the management of urethral and prostatic neoplasia in 6 dogs. Vet Surg 2004;33:505-516.

30. Goya N, Ishikawa N, Tomizawa Y, et al. Electrovaporization using a rollerball electrode for flat or small papillary tumors of the bladder: basic study in dogs. J Endourol 2001;15:951-955.

31. Knapp DW, Richardson RC, Chan TC, et al. Piroxicam therapy in 34 dogs with transitional cell carcinoma of the urinary bladder. J Vet Intern Med 1994;8:273-278.

32. Mutsaers AJ, Mohammed SI, DeNicola DB, et al. Pretreatment tumor prostaglandin E2 concentration and cyclooxygenase-2 expression are not associated with the response of canine naturally occurring invasive urinary bladder cancer to cyclooxygenase inhibitor therapy. Prostaglandins Leukot Essent Fatty Acids 2005;72:181-186.

33. Chun R, Knapp DW, Widmer WR, et al. Cisplatin treatment of transitional cell carcinoma of the urinary bladder in dogs: 18 cases (1983-1993). J Am Vet Med Assoc 1996;209:1588-1591.

34. Moore AS, Cardona A, Shapiro W, et al. Cisplatin (cisdiamminedichloroplatinum) for treatment of transitional cell carcinoma of the urinary bladder or urethra. A retrospective study of 15 dogs. J Vet Intern Med 1990;4:148-152.

35. Shapiro W, Kitchell BE, Fossum TW, et al. Cisplatin for treatment of transitional cell and squamous cell carcinomas in dogs. J Am Vet Med Assoc 1988;193:1530-1533.

36. Chun R, Knapp DW, Widmer WR, et al. Phase II clinical trial of carboplatin in canine transitional cell carcinoma of the urinary bladder. J Vet Intern Med 1997;11:279-283.

37. Hammer AS, Couto CG, Ayl RD, et al. Treatment of tumor-bearing dogs with actinomycin D. J Vet Intern Med 1994;8:236-239.

38. Rocha TA, Mauldin GN, Patnaik AK, et al. Prognostic factors in dogs with urinary bladder carcinoma. J Vet Intern Med 2000;14:486-490.

39. Henry CJ, McCaw DL, Turnquist SE, et al. Clinical evaluation of mitoxantrone and piroxicam in a canine model of human invasive urinary bladder carcinoma. Clin Cancer Res 2003;9:906-911.

40. Ogilvie GK, Obradovich JE, Elmslie RE, et al. Efficacy of mitoxantrone against various neoplasms in dogs. J Am Vet Med Assoc 1991;198:1618-1621.

41. Helfand SC, Hamilton TA, Hungerford LL, et al. Comparison of three treatments for transitional cell carcinoma of the bladder in the dog. J Am Anim Hosp Assoc 1994;30:270-275.

42. Boria PA, Glickman NW, Schmidt BR, et al. Carboplatin and piroxicam therapy in 31 dogs with transitional cell carcinoma of the urinary bladder. Vet Comp Oncol 2005;3:73-80.

43. Sharifi R, Lee M, Clayton M, et al. Phase I-II evaluation of intravesical novantrone (mitoxantrone) in superficial bladder cancer. Anticancer Drugs 1991;2:153-157.

44. Namasivayam S, Whelan P. Intravesical mitozantrone in recurrent superficial bladder cancer: a phase II study. Br J Urol 1995;75:740-743.

45. Poirier VJ, Forrest LJ, Adams WM, et al. Piroxicam, mitoxantrone, and coarse fraction radiotherapy for the treatment of transitional cell carcinoma of the bladder in 10 dogs: a pilot study. J Am Anim Hosp Assoc 2004;40:131-136.

46. Withrow SJ, Gillette EL, Hoopes PJ, et al. Intraoperative irradiation of 16 spontaneously occurring canine neoplasms. Vet Surg 1989;18:7-11.

47. Walker M, Breider M. Intraoperative radiotherapy of canine bladder cancer. Vet Radiol 1987;28:200-204.

48. Anderson CR, McNiel EA, Gillette EL, et al. Late complications of pelvic irradiation in 16 dogs. Vet Radiol Ultrasound 2002;43:187-192.

49. de Lorimier LP, Fan TM. Treating cancer pain in dogs and cats. Vet Med 2005;100:364-379.

50. Stiffler KS, McCrackin Stevenson MA, Cornell KK, et al. Clinical use of low-profile cystostomy tubes in four dogs and a cat. J Am Vet Med Assoc 2003;223:325-329.

51. Salinardi BJ, Marks SL, Davidson JR, et al. The use of a low-profile cystostomy tube to relieve urethral obstruction in a dog. J Am Anim Hosp Assoc 2003;39:403-405.

52. Fan TM, de Lorimier LP, Charney SC, et al. Evaluation of intravenous pamidronate administration in 33 cancer-bearing dogs with primary or secondary bone involvement. J Vet Intern Med 2005;19:74-80.

53. Thrall DE, LaRue SM. Palliative radiation therapy. Semin Vet Med Surg (Small Anim) 1995;10:205-208.

54. Kassouf W, Dinney CP, Brown G, et al. Uncoupling between epidermal growth factor receptor and downstream signals defines resistance to the antiproliferative effect of Gefitinib in bladder cancer cells. Cancer Res 2005;65:10524-10535.

55. Ridgway TD, Lucroy MD. Phototoxic effects of 635-nm light on canine transitional cell carcinoma cells incubated with 5-aminolevulinic acid. Am J Vet Res 2003;64:131-136.

56. Skyrme RJ, French AJ, Datta SN, et al. A phase-1 study of sequential mitomycin C and 5-aminolaevulinic acid-mediated photodynamic therapy in recurrent superficial bladder carcinoma. BJU Int 2005;95:1206-1210.

57. Lamm DL, McGee WR, Hale K. Bladder cancer: current optimal intravesical treatment. Urol Nurs 2005;25:323-326.

58. Cozzi PJ, Bajorin DF, Tong W, et al. Toxicology and pharmacokinetics of intravesical gemcitabine: a preclinical study in dogs. Clin Cancer Res 1999;5:2629-2637.

59. van der Meijden AP, Steerenberg PA, de Jong WH, et al. The effects of intravesical and intradermal application of a new B.C.G. on the dog bladder. Urol Res 1986;14:207-210.

60. Smith SD, Wheeler MA, Plescia J, et al. Urine detection of survivin and diagnosis of bladder cancer. J Am Med Assoc 2001;285:324-328.

61. Henry CJ, University of Missouri, Columbia: Personal communication, April 2006.