Transitional cell carcinoma of the urinary bladder in a 14-year-old dog

Abstract

A 14-year-old spayed female poodle-pekinese dog with a history of hematuria was tentatively diagnosed with non-radiopaque uroliths or urinary bladder neoplasia following temporary resolution of clinical signs after several rounds of antibiotic treatments, normal abdominal radiographs and no growth on urine culture. Abdominal ultrasound revealed a mass in the trigone area of the urinary bladder which was confirmed to be an invasive transitional cell carcinoma by histopathology following euthanasia.

Case description

A 14-year-old spayed female poodle-pekinese crossbred dog was presented for evaluation of hematuria. Urinalysis revealed dark-brown, turbid urine containing a high number of red blood cells (too numerous to count) and 6 to 9 transitional epithelial cells with clumps in each high power field (hpf). No bacteria or crystals were observed. The abdomen was tense on palpation, and the urinary bladder was firm. The remainder of the physical examination was unremarkable. Antimicrobial therapy was instituted with enrofloxacin (Baytril; Bayer Animal Health, Shawnee Mission, Kansas, USA), 5 mg/kg, PO, q24h for 14 d. Ten days later, amoxicillin/clavulanic acid (Clavaseptin; Vétoquinol, Princeville, Québec), 6.25 mg/kg, PO, q12h for 14 d was administered in addition to enrofloxacin for their synergistic effects.

One month later, the owner reported that the antibiotics had temporarily resolved the hematuria, but that she had once again noticed red tinged urine, darker than before. A second course of antibiotics was prescribed: amoxicillin/clavulanic acid (Clavaseptin; Vétoquinol), 6.25 mg/kg, PO, q12h for 14 d. It was later determined that the owner was giving the antibiotics incorrectly, and only half of the prescribed dose had been administered. A lateral survey radiograph of the abdomen revealed no abnormalities. No radiopaque uroliths were detected. One week after completion of the second course of antibiotics, the owner again reported hematuria and requested more antibiotics. A third course of antibiotics was prescribed: amoxicillin/clavulanic acid (Clavaseptin; Vétoquinol), 6.25 mg/kg, PO, q12h for 14 d.

One week following completion of the third course of antibiotics, hematuria was still evident. On physical examination, the abdomen was soft and easily palpated with no masses or discomfort detected. Auscultation of the heart revealed a grade 3-4/6 systolic heart murmur audible bilaterally with the point of maximal intensity over the left apex. The owner reported pollakiuria. Urine was collected by cystocentesis and sent to a laboratory (IDEXX, Markham, Ontario) for urinalysis and culture. A fourth course of amoxicillin/clavulanic acid (Clavaseptin; Vétoquinol), at a higher dosage (8.3 mg/kg, PO, q12h for 14 d) was prescribed. The urine was yellow and turbid and contained a significant number of red blood cells (4+), 3 to 5 WBC/hpf, 1 to 5 transitional epithelial cells/hpf, 1 to 5 squamous epithelial cells/hpf, the pH was 6.5, protein was 2+, and the specific gravity was 1.023. No bacteria or crystals were observed. There was no growth on urine culture, suggesting either non-radiopaque uroliths or neoplasia.

Two weeks later the owner reported that there was no change in the hematuria or pollakiuria; however, once again, only half of the prescribed dose of antibiotic had been administered. Ultrasound examination of the urinary bladder was advised. A pre-anesthetic blood screen revealed elevated alkaline phosphatase (ALP) of 731 U/L [reference interval (RI): 23 to 212 U/L], alanine transferase (ALT) of 660 U/L (RI: 10 to 100 U/L), cholesterol of 11.68 mmol/L (RI: 2.84 to 8.27 mmol/L), urea of 11.1 mmol/L (RI: 2.5 to 9.6 mmol/L) and potassium of 6.4 mmol/L (RI: 3.5 to 5.8 mmol/L). A complete blood (cell) count (CBC) revealed a moderate elevation of platelets but no other abnormal findings.

The ultrasound image revealed a knobby hyperechoic mass in the trigone area leading to a patent urethra (Figure 1). The body and base of the bladder wall appeared normal. A tentative diagnosis of transitional cell carcinoma was made, and a biopsy of the tumor by urethral catheter was recommended to confirm the diagnosis. Findings were discussed with the owner and options of humane euthanasia or palliative treatment with a non-steroidal anti inflammatory drug (NSAID) were presented. Meloxicam (Metacam 3 mg/mL; Schering-Plough Animal Health, Union, New Jersey, USA), 0.125 mg/kg, PO, q24h was prescribed, and frequent monitoring of liver and renal function (every 4 wk) was recommended based on the pre-anesthetic blood screen abnormalities. Two days later the owner reported dark urine and weakness, and a physical examination was recommended.

Figure 1.

Ultrasound image of the urinary bladder of the dog. A knobby hyperechoic mass in the trigone area is outlined and labelled as tumor on the image. This finding is consistent with transitional cell carcinoma.

Six weeks later, the dog was presented for evaluation of decreased responsiveness and inability to stand. The owner reported that the dog was less responsive and energetic, inappetent, had an occasional cough and had vomited that morning. No blood had been detected in the urine over the past 3 wk. On physical examination, the dog was quiet and less responsive than on previous visits. A weight loss of 0.4 kg in 1.5 mo, and 5% to 7% dehydration were noted. On auscultation, the heart sounds were muffled, but no crackles or wheezes were detected within the lung fields. On palpation, the abdomen was tense and distended, the bladder was enlarged but not firm. The dog was in sternal recumbency with rotation to the left, had marked proprioceptive deficits in both hind limbs, withdrawal reflexes were slow but intact, and no neck or back pain was observed. The dog refused to walk, and was humanely euthanized at the request of the owner.

A focused postmortem examination was conducted during which the entire urinary bladder and sections of kidney and liver were collected and sent to the Animal Health Laboratory, University of Guelph, for histopathology. The histological report revealed a plaque on the mucosa of the urinary bladder composed of closely packed neoplastic cells that infiltrated the submucosa. There was marked anisokaryosis/anisocytosis with 51 mitoses per 10 high power fields. This confirmed an invasive transitional cell carcinoma of the urinary bladder. The kidney showed an increase in mesangial matrix in most glomeruli, and the interstitium was edematous with very early fibrosis and random small lymphoplasmacytic infiltrates. These findings were consistent with chronic membranous glomerulopathy with mild interstitial edema and early fibrosis. The liver showed changes consistent with chronic mild hepatopathy with cholangiolar proliferation.

Discussion

Tumors of the urinary bladder and urethra account for < 1% of all canine cancers (1,2). Transitional cell carcinoma (TCC), however, accounts for 50% to 75% of reported cases of canine urinary bladder cancer (3). According to data collected from the American National Cancer Institute between 1975 and 1995, the prevalence of bladder cancer in dogs is on the rise (4). The etiology of TCC is not completely understood, and is likely multifactorial (1,2). Many risk factors have been identified and include exposure to topical insecticides (this risk is increased in overweight dogs), marshes sprayed for mosquito control, and level of industrial activity (1,2,4). Prevalence appears to be higher in certain breeds including the Scottish terrier, beagle, and airedale terrier (1,2,4). This is likely due to a genetic predisposition affecting, for example, the makeup of biochemical pathways related to carcinogen detoxification (4). Transitional cell carcinoma is also seen more commonly in females than in males (1,2,4), possibly because male dogs have more frequent urinations due to territorial marking, thus decreasing potentially carcinogen containing urine contact time with the bladder epithelium (4). Increased body fat and thus increased storage of lipophilic environmental carcinogens in females may also contribute to this finding (4).

Clinical signs of TCC are most commonly forms of dysuria including hematuria, stranguria, and pollakiuria (1,2). In some cases there is improvement of clinical signs with the use of antibiotics (2) as was encountered in this case. Less commonly, weight loss, lethargy, and lameness may be seen (4). Advanced cases may present with signs of bladder rupture, such as a distended and painful abdomen (2). Transitional cell carcinoma tends to be seen in older dogs, with 1 study reporting a mean age of 11.1 y at diagnosis (1,2). In some cases there are no abnormal findings on physical examination (1). Tumors are most commonly found in the trigone region of the urinary bladder (2,4).

Over the past few years, tumor antigen screening tests for TCC have been developed, but have low sensitivity and specificity (4). Other methods of detection of TCC include radiography (double contrast cystography) and ultrasound examination. With contrast cystography, a mass or filling defect was observed in 96% of cases examined in 1 study (1). Transitional cell carcinoma may be indistinguishable from cystitis on urinalysis (2). Increased red blood cells, white blood cells, and bacteria may be observed in the urine in both conditions (2). Urine sediment reveals tumor cells in only 30% of cases (1). Definitive diagnosis can be achieved through histopathologic examination of a tissue sample obtained by cystotomy, cystoscopy, or a catheter biopsy (4). Care must be taken when collecting a biopsy sample as transplantation of tumor cells has been reported after surgical manipulation (2,4). Death is most commonly due to urinary tract obstruction when the primary tumor is not treated; this generally occurs prior to metastasis (4).

In a study of 74 dogs with TCC, most tumors were papillary infiltrative, and either histologic grade 2 (81%) or 3 (16%) (5). In another study, however, histologic diagnosis did not correlate with prognosis (6). Cyclooxygenase-2 (COX-2) and P-glycoprotein (P-gp) are expressed in 57.7% and 76.9% of cases of TCC, respectively (3). COX-2 is not expressed in normal urinary bladder epithelium (4). This is relevant in the treatment of TCC tumors because piroxicam, a COX inhibitor, has been documented to induce remission (4).

Due to the progressive nature of this disease, most treatment is palliative. Surgical excision of most tumors is difficult due to their location and proximity to the ureters. A median postsurgical survival time of 125 d has been reported in 23 dogs after surgical debulking of the primary tumor (1).

Several other surgical techniques have been described including ureterocolonic anastomosis; however, complications were common, and survival times of only 60 d were achieved with this method of treatment in 1 study (4). More recently, a technique was described in which circumferential excision of the bladder neck and proximal urethra was done while successfully preserving the neurovascular pedicles, and did not cause urinary incontinence or bladder wall necrosis (7). Other treatment options include chemotherapy, with most success achieved by using combination protocols. One study reported median survival times of 259 d in 11 dogs with the use of doxorubicin along with cyclophosphamide (4). Non-steroidal anti-inflammatory drug (NSAID) therapy with piroxicam is gaining increasing consideration, as it is thought to cause TCC remission by induction of apoptosis (2,4,6). A median survival time of 180 d in 62 dogs has been reported with the use of piroxican (4). Piroxicam is also commonly combined with chemotherapeutic agents, such as mitoxantrone, which induces remission more frequently when used in conjunction rather than either drug on its own (8). Carbon dioxide laser ablation has also been used in combination with mitoxantrone and piroxicam treatment; however, survival times were similar to those achieved using chemotherapy alone (9).

A study on the effects of dietary vegetable consumption for reducing the risk of TCC revealed an inverse association between consumption of vegetables at least 3 times per week and the risk of developing TCC (10). This was true of green leafy vegetables and yellow-orange vegetables; however, cruciferous vegetable consumption did not show the same association (10).

This case highlights the importance of patient follow-up, and client communication to ensure that the proper dosage of prescription medication is being given to the patient. Because no bacteria were cultured from the urine in this case, it is unlikely that the inaccurate dosing had any serious implications. Culturing the urine at presentation may have led to a more rapid diagnosis of neoplasia by ruling out bacterial infection. This case also showed the value of ultrasound examination in making a tentative diagnosis of TCC. Treatment options such as chemotherapeutic drugs or use of the NSAID piroxicam may have prolonged this dog’s survival time.