Lower urinary tract transitional cell carcinoma in cats: Clinical findings, treatments, and outcomes in 118 cases (2024)

Abbreviations

BUN

blood urea nitrogen

CI

confidence interval

COX

cyclooxygenase

FNA

fine‐needle aspirate

HR

hazard ratio

IQR

interquartile range

NSAIDs

nonsteroidal anti‐inflammatory drugs

OR

odds ratio

TCC

transitional cell carcinoma

2.1. Case selection criteria

A retrospective study was performed. The medical record databases of 11 referral veterinary clinics (9 academic teaching hospitals and 2 private practice hospitals) were searched to identify cats with lower urinary tract carcinoma that were presented to clinicians of various specialty disciplines. To be included, cats were required to have cytological or histopathological confirmation of carcinoma from a mass in either the bladder or urethra.

2.2. Medical records review

Variables obtained from the medical records included signalment, history of lower urinary tract disease, clinical signs and duration of clinical signs, physical examination findings, clinical pathology and urine culture results, diagnostic imaging results, treatments pursued (surgery, nonsteroidal anti‐inflammatory drugs (NSAIDs), chemotherapy, radiation therapy, and urethral or ureteral stent placement), documented complications and adverse events, cytology and histopathology results, progression (ie, growth of primary tumor or recurrence) of disease, documentation of metastatic disease, and timing and cause of death. Complications were considered major if they required intensive care, revision surgery, or both; all other complications were considered minor.

2.3. Statistical analysis

Descriptive statistics were calculated, using tests of skewness and kurtosis to evaluate normal distribution for continuous variables. Multivariable logistic regression was used to model risk factors associated with receiving no treatment. Univariable analyses were performed first and variables with P < .2 were tested in the final model. Variables were retained in the multivariable model if P < .05 or if incorporation changed odds ratios (OR) by >15%. The Kaplan‐Meier product limit method was used to estimate median progression‐free survival (time from initial presentation to the study institution until the first instance of documented progression, regional or distant metastasis, or death) and overall survival (time from initial presentation to the study institution until death). Cats that did not reach these endpoints or were lost to follow‐up were censored in the respective analyses. Log rank test for trend across ordered groups was used to compare unadjusted survival across the following treatment groups: no treatment, treatment that did not include partial cystectomy, and treatment that included partial cystectomy. Multivariable COX regression was used to model risk factors associated with overall survival time as measured from the date of initial presentation to the contributing hospital. Similarly, univariable analyses were performed first and variables with P < .2 were tested in the final model. Variables were retained in the multivariable model if P < .05 or if incorporation changed hazard ratios (HR) by >15%. Statistical software (Stata version 14.2, College Station, Texas) was used for all analyses, and P < .05 was considered statistically significant.

3.1. Cats

Between 1991 and 2018, 118 cats from 11 institutions met inclusion criteria. The contributing veterinary clinics were as follows: University of California‐Davis, School of Veterinary Medicine; Colorado State University, College of Veterinary Medicine; University of Pennsylvania, School of Veterinary Medicine; University of Tennessee, College of Veterinary Medicine; Oregon State University, Carlson College of Veterinary Medicine; University of Georgia, College of Veterinary Medicine; North Carolina State University, College of Veterinary Medicine; VCA Canada—Alta Vista Animal Hospital; University of Illinois, College of Veterinary Medicine; University of Guelph, Ontario Veterinary College; and, Blue Pearl, Seattle Veterinary Specialists. The median age of included cats was 15.0 years (interquartile range [IQR], 13.0‐17.0; range, 5.0‐20.8 years). Cat breeds included 74 of 118 (62.7%) domestic shorthair, 18 of 118 (15.3%) domestic longhair, 10 of 118 (8.5%) domestic medium hair, 5 of 118 (4.2%) Siamese or Siamese Cross, and 2 of 118 (1.7%) each of Abyssinian, Persian, and Himalayan; 5 of 118 (4.2%) cats were other breeds. Sex included 62 of 117 (53.0%) spayed females, 54 of 117 (46.2%) castrated males, and 1 of 117 (0.9%) intact female; sex data was not provided for 1 cat.

3.2. Lower urinary tract disease history and clinical signs

A history of urinary tract infection was present in 28 of 118 (23.7%) cats, feline idiopathic cystitis in 17 of 118 (14.4%) cats, and urolithiasis in 12 of 118 (10.2%) cats. The majority of cats (92/118; 78.0%) had previously been presented to a veterinarian for signs of urinary tract disease. At least 1 clinical sign was noted in 111 of 118 (94.1%) cats, and the median duration of clinical signs was 30 days (IQR, 9‐105; range, 0‐730 days). For the remaining 7 of 118 (5.9%) cats, TCC was found incidentally during diagnostic imaging for assessment of other disease processes. Clinical signs included hematuria in 74 of 118 (62.7%), pollakiuria in 59 of 118 (50.0%), stranguria in 57 of 118 (48.3%), anorexia in 26 of 118 (22.0%), lethargy in 26 of 118 (22.0%), vomiting in 23 of 118 (19.5%), and abdominal pain in 12 of 118 (10.2%) cats. Of cats with these clinical signs, 27 of 111 (24.3%) had 1 sign, 31 of 111 (27.9%) had 2 signs, 36 of 111 (32.4%) had 3 signs, 11 of 111 (9.9%) had 4 signs, 2 of 111 (1.8%) had 5 signs, 2 of 111 (1.8%) had 6 signs, and 2 of 111 (1.8%) had 7 signs. Urethral obstruction at presentation was noted in 12 of 118 (10.2%) cats.

3.3. Physical examination

At initial evaluation, cats had a median weight of 4.0 kg (IQR, 3.3‐5.2; range, 2.1‐11.8 kg) and median body condition score of 5 of 9 (IQR, 3‐6; range, 1‐9/9). On abdominal palpation, 25 of 118 (21.2%) cats were painful, and 22 of 118 (18.6%) cats had a palpable mass or thickening of the urinary bladder region.

3.4. Diagnostic results

Clinicopathologic results (CBC and serum biochemistry panel) were available for 102 cats at initial evaluation by the contributing clinic; 94 of 102 samples (92.2%) were obtained before IV fluid administration, and 8 of 102 samples (7.8%) were obtained during or after IV fluid administration. Decreased hematocrit, increased serum creatinine and increased blood urea nitrogen (BUN) concentrations were noted in 31 of 102 (30.4%), 34 of 102 (33.3%), and 58 of 102 (56.9%) cats, respectively. Median BUN concentration was 43 mg/dL (IQR, 32‐58; range, 14‐262), and median serum creatinine concentration was 1.9 mg/dL (IQR, 1.5‐2.6; range, 4.5‐15.6). Urinalysis was available for 69 cats. Median urine specific gravity was 1.016 (IQR 1.012‐1.025, range 1.000‐1.056). Urine culture was performed on 67 cats at initial evaluation by the contributing clinic; culture was performed on samples obtained from voided samples in 10 of 67 (14.9%), cystocentesis in 25 of 67 (37.3%), catheterization in 1 of 67 (1.5%) cats, and method of collection was not reported in 31 of 67 (46.3%) cats. Urine culture was positive for bacterial growth in 10 of 67 (14.9%) cats; organisms cultured included E. coli alone (5/10; 50%), E. coli and Enterococcus (1/10; 10%), E. coli and Bacillus (1/10; 10%), Enterococcus alone (1/10; 10%), Enterococcus and Staphylococcus (1/10; 10%), and Serratia marcescens (1/10; 10%).

Abdominal ultrasound examination, thoracic radiographs, abdominal radiographs, and cystoscopy were performed on 110 of 118 (93.2%), 70 of 118 (59.3%), 25 (21.2%), and 5 (4.2%) cats respectively; abdominal computed tomography was not performed on any cat. Diagnostic images were reviewed and interpreted by board‐certified radiologists. Ultrasonographic findings included a single bladder mass (95/110; 86.4%), bladder wall thickening with a mass (8/110; 7.3%), and multiple bladder masses (7/110; 6.4%). Tumors were located in the trigone in 32 of 118 (27.1%), ventral bladder wall in 28 of 118 (23.7%), bladder apex in 20 of 118 (17.0%), dorsal bladder wall in 16 of 118 (13.6%), multifocal or diffuse throughout the urinary bladder in 10 of 118 (8.5%), and lateral bladder wall in 3 of 118 (2.5%) cats; tumor location was not reported in 9 of 118 (7.6%) cats. Urethral involvement of the tumor was documented by ultrasound examination or cystoscopy in 14 of 118 (11.9%) cats, 1 of 14 (7.1%) cats of which were obstructed. Ureteral obstruction was diagnosed in 14 of 118 (11.9%) cats by ultrasound examination, and 6 of 118 (5.1%) cats had evidence of both urethral and ureteral involvement (with 1 cat diagnosed with both urethral and ureteral obstruction). Of the 5 cats that underwent cystoscopy, cystoscopy allowed for visualization and further characterization of the TCC lesion in the lower urinary tract in 4 of 5 (80.0%) cats and resulted in poor visualization without detection of clinically relevant abnormalities in 1 cat.

Cytology results, acquired by fine‐needle aspirate (FNA), urine cytospin, or traumatic urethral catheterization and reviewed by board‐certified pathologists, were available for 78 of 118 (66.1%) cats and were consistent with TCC in 33 of 78 (42.3%) samples, carcinoma in 26 of 78 (33.3%) samples, or other (including epithelial hyperplasia, proliferation, or atypia [6/78; 7.7%], inflammation [2/78; 2.6%], probable neoplasia [2/78; 2.6%], inflammation with epithelial hyperplasia or atypia [2/78; 2.6%], normal transitional epithelial cells [1/78; 1.3%], sarcoma [1/78; 1.3%], and lymphosarcoma vs. carcinoma [1/78; 1.3%]) in 15 of 78 (19.2%) samples, and were inconclusive in 4 of 78 (5.1%) samples. Histopathology, obtained by surgical biopsy, cystoscopic biopsy, necropsy, or some combination of these, was available for 62 of 118 (52.5%) cats; definitive diagnosis was obtained by cytology without histopathology in 56 of 118 (47.5%) cats. Tumors were described as infiltrative in 43 of 62 (69.4%), high grade in 2 of 62 (3.2%), and low grade in 1 of 62 (1.6%) histopathologic samples. Tumors were not described as in situ or aneuploid in any reports. Prostaglandin E measurements and cyclooxygenase (COX) expression were not reported for any tumor. Diagnosis was obtained by ultrasound‐guided FNA alone in 33 of 118 (28.0%) cats, surgical biopsy alone in 30 of 118 (25.4%) cats, necropsy alone in 17 of 118 (14.4%) cats, urine cytospin alone in 14 of 118 (11.9%) cats, and traumatic urethral catheterization alone in 6 of 118 (5.1%) cats. Several cats had multiple diagnostic tests performed (agreement was not noted between cytology and biopsy in all cases): ultrasound‐guided FNA and urine cytospin in 5 of 118 (4.2%) cats, ultrasound‐guided FNA and surgical biopsy in 4 of 118 (3.4%) cats, ultrasound‐guided FNA and necropsy in 3 of 118 (2.5%) cats, cystoscopic biopsy and surgical biopsy in 2 of 118 (1.7%) cats, cystoscopic biopsy and traumatic urethral catheterization in 1 cat, urine cytospin and surgical biopsy in 1 cat, urine cytospin and necropsy in 1 cat, and a combination of urine cytospin, traumatic urethral catheterization, cystoscopic biopsy, and surgical biopsy in 1 cat.

Based on imaging, cytology, and histopathology results, 15 of 118 (12.7%) cats were considered to have metastatic disease at initial evaluation; 9 of 118 (7.6%) cats had metastasis to regional lymph nodes alone, 3 of 118 cats (2.5%) had abdominal carcinomatosis, 1 cat had metastasis to a regional lymph node and omental tissue near the bladder, 1 cat had presumed pulmonary metastasis based on thoracic radiographs, and 1 cat had both regional lymph node and presumed pulmonary metastasis based on thoracic radiographs. Cases of nonpulmonary metastasis were confirmed by cytology or histopathology, whereas cases of pulmonary metastasis were reported as suspected based on radiographic interpretation by a board‐certified radiologist.

3.5. Treatment

Information regarding treatment (specifically cystectomy) is found in Table ​Table1.1. Of the 2 cats with trigonal tumors that underwent partial cystectomy, ureteral reimplantation was performed on 1 cat and resection of a ureteral papilla was performed on the other cat. The median estimated percentage of bladder wall excised during partial cystectomy (reported in 15/28 [53.6%] cats) was 50% (range, 20%‐65%). Radical cystectomy was not performed on any cat. Surgical biopsy without partial cystectomy was performed on 7 of 118 (5.9%) cats. Tumor location of cats undergoing surgical biopsy included dorsal wall (2/7; 28.6%), trigone with extension into the ureters (1/7; 14.3%), dorsal and ventral wall (1/7; 14.3%), and multifocal or diffuse (1/7; 14.3%); location was not reported in 1 cat. Excision was reportedly complete (ie, tumor‐free margins on histopathology) after 9 of 28 (32.1%) partial cystectomies, incomplete (ie, tumor cells extending to margins on histopathology) after 12 of 28 (42.9%) partial cystectomies, and not reported after 7 of 28 (25.0%) partial cystectomies. Four cats had documented margins of normal bladder tissue with a histopathologically complete excision, and a range of 1 to 3 mm of normal bladder wall was noted.

Three major postoperative complications occurred (septic peritonitis [2/28; 7.1%] and uroperitoneum [1/28; 3.6%]) and 3 minor complications occurred (transient urinary incontinence [1/28; 3.6%], massive abdominal wall bruising [1/28; 3.6%], and hematuria and stranguria[(1/28; 3.6%] in cats undergoing partial cystectomy. Of the 2 cats with trigonal tumors that underwent partial cystectomy, both experienced major postoperative complications (septic peritonitis [1/2; 50%] and uroperitoneum [1/2; 50%]). One cat that underwent surgical biopsy without cystectomy had a major complication; during surgery, a cystostomy tube was placed and leakage of the cystostomy tube (requiring revision surgery) was encountered postoperatively.

Improvement in clinical signs was reported after surgery in 21 of 28 (75.0%) cats that underwent partial cystectomy, but it is unknown if this improvement can be completely attributed to surgery because many cats underwent multimodality therapy. No improvement in clinical signs was reported after surgery in 2 of 28 (7.1%) cats that underwent partial cystectomy. Data regarding improvement was not available for the remaining 5 cats that underwent partial cystectomy. After partial cystectomy, 12 of 28 (42.9%) cats received no additional treatment, 7 of 28 (25.0%) cats received NSAIDs only, 6 of 28 (21.4%) cats received chemotherapy and NSAIDs, and 3 of 28 (10.7%) cats received chemotherapy only.

Nonsteroidal anti‐inflammatory drugs were administered to 49 of 118 (41.5%) cats; 15 of 49 (30.6%) cats were treated only with NSAIDs, and 34 of 49 (69.4%) cats were treated with NSAIDs as part of a multiple modality treatment plan. Administered NSAIDs included piroxicam only in 30 of 49 (61.2%) cats, meloxicam only in 14 of 49 (28.6%) cats, robenacoxib only in 3 of 49 (6.1%) cats, and both piroxicam and meloxicam (sequential) in 2 of 49 (4.1%) cats. Adverse events were reported in 13 of 49 (26.5%) cats prescribed NSAIDs and included acute onset or progression of azotemia (6/13; 46.2%), nausea, vomiting, or regurgitation (3/13; 23.1%), inappetence (2/13; 15.4%), diarrhea with or without melena (2/13; 15.4%), lethargy (1/13; 7.7%), constipation (1/13; 7.7%), and hematuria (1/13; 7.7%). However, documentation of these clinical signs as directly associated with NSAID administration was not possible in at least 7 of 13 (53.8%) cats because of other concurrent treatments or progressive disease.

Chemotherapy was administered to 33 of 118 (28.0%) cats; 6 of 33 (18.2%) cats were treated with only chemotherapy and 27 of 33 (81.8%) cats were treated with chemotherapy as part of multimodality (ie, surgery, NSAID administration, radiation therapy, or some combination of these) treatment plan. The most common chemotherapy protocol was mitoxantrone alone (17/33; 51.5%). Other protocols included carboplatin alone (4/33; 12.1%); mitoxantrone and vinblastine (2/33; 6.1%); mitoxantrone and chlorambucil (2/33; 6.1%); chlorambucil alone (2/33; 6.1%); vinblastine alone (1/33; 3.0%); doxorubicin and carboplatin (1/33; 3.0%); mitoxantrone and carboplatin (1/33; 3.0%); mitoxantrone and cyclophosphamide (1/33; 3.0%); mitoxantrone, vinblastine, and gemcitabine (1/33; 3.0%); and, mitoxantrone, carboplatin, and vinblastine (1/33; 3.0%). For each protocol with multiple chemotherapy agents utilized, administration of the agents was sequential rather than concurrent. Mitoxantrone was administered as a first‐line chemotherapy agent in 24 of 33 (72.7%) cats. Adverse events were reported in 23 of 33 (69.7%) cats given chemotherapy; grading of neutropenia was based on definitions used by the Veterinary Co‐operative Oncology Group—Common Terminology Criteria for Adverse Events. Adverse events included gastrointestinal signs, lethargy, or both (21/23; 91.3%), myelosuppression (5/23 [21.7%]; grade II neutropenia in 1/5 [20.0%], grade III neutropenia in 3/5 [60.0%], grade IV neutropenia in 1/5 [20.0%]), and azotemia (6/23 [26.1%] with at least 2/6 [33.3%] of these cases possibly attributed to another cause of renal injury because azotemia was present before chemotherapy). Reported clinical response rate (ie, improvement of clinical signs) was 25 of 33 (75.8%) in cats given chemotherapy as part of their treatment protocol. However, all but 6 of 33 (18.2%) cats underwent other forms of treatment, and in those cats, improvement in clinical signs cannot be attributed to chemotherapy alone. In the 6 cats that received chemotherapy alone, clinical signs improved in 2 of 6 (33.3%) cats, but information regarding the response in the other 4 of 6 (66.7%) cats was not available.

Radiation therapy was administered to 3 of 118 (2.5%) cats on a once weekly fractionated basis for 2 to 6 treatments; 2 of 3 (66.7%) cats were treated with only radiation therapy and 1 cat was treated with radiation therapy and NSAIDs. One cat received 5 fractions of 6 Gy on a weekly basis, and 1 cat received 6 fractions (dose not reported); both cats experienced improvement in clinical signs. One additional cat received 2 fractions of 6 Gy, and radiation therapy subsequently was discontinued because of reported lack of improvement of clinical signs. One cat was treated using urethral and ureteral stents in addition to chemotherapy. In 1 additional cat, placement of a ureteral stent was unsuccessful.

On multivariable analysis, trigonal disease (OR, 3.91; 95% confidence interval [CI], 1.40‐10.9) and a presenting complaint of lethargy (OR, 3.54; 95% CI, 1.26‐9.99) increased the odds of not receiving treatment. Body weight, age, sex, BUN concentration, serum creatinine concentration, anorexia, hematuria, vomiting, pollakiuria, stranguria, metastasis at presentation, and duration of clinical signs were not significantly associated with receiving treatment.

3.6. Outcome

Median follow‐up time starting from the first visit was 63 days (range, 0‐2095 days), and this calculation included 15 untreated cats that were euthanized at the time of the first visit. Median progression‐free survival time was 113 (95% CI, 69‐153) days. Data pertaining to tumor progression was available for 81 of 118 (68.6%) cats; 45 of 81 (55.6%) cats had documented progression at a median of 116 days (range, 3‐459 days). Documented progression occurred in 9 of 31 (29.0%) untreated cats, 22 of 28 (78.6%) cats treated without partial cystectomy, and 14 of 22 (63.6%) cats that underwent partial cystectomy, including 4 of 9 (44.4%) cats that reportedly had completely excised tumors based on histopathology findings. The median time to tumor recurrence in cats that underwent partial cystectomy was 205 days (range, 42‐459 days). Development or increased size of regional or distant metastatic disease, or both was documented in 11 of 66 (16.7%) cats with available data at a median of 176 days (range, 43‐407 days). The sites of metastatic progression included lungs (4/11; 36.4%), lymph nodes (3/11; 27.3%), abdominal carcinomatosis (3/11; 27.3%), tissue adjacent to the urinary bladder ([possible body wall] 2/11; 18.2%), kidney and ureter (1/11; 9.1%), pancreas (1/11; 9.1%), liver (1/11; 9.1%), omentum (1/11; 9.1%), small intestine (1/11; 9.1%), and sacral vertebra (1/11; 9.1%). Necropsy was performed on 31 of 118 (26.3%) cats, and metastatic disease was documented in 6 of 31 (19.4%) cats on necropsy examination. Sites of metastatic disease on necropsy included kidneys, liver, and abdominal lymph nodes (1/6; 16.7%); pancreas (1/6; 16.7%); lungs, pancreatic lymph nodes and mesentery, renal capsule, abdominal lymph nodes, and lymphatic and vascular obstruction with development of chyloabdomen (1/6; 16.7%); and, carcinomatosis (3/6; 50.0%). Overall, at study completion, metastatic disease was documented in 25 of 118 (21.2%) cats (including both cats that had metastatic disease at the time of presentation and those that developed metastatic disease at a later date). One cat with suspected tumor extension into the ventral body wall had a prior FNA performed for evaluation of the bladder tumor (no surgery was performed on this cat). Two cats that developed abdominal carcinomatosis also previously had FNA performed for evaluation of the bladder tumor (no surgery was performed on these cats), and 1 cat that developed abdominal carcinomatosis previously underwent celiotomy without cystectomy.

At the time of analysis, 4 of 118 (3.4%) cats were alive, 77 of 118 (65.3%) cats were dead, and 37 of 118 (31.4%) cats were lost to follow‐up at a median of 30 days post‐visit (IQR, 8‐180; range, 1‐541). Of the deceased cats, 68 of 77 (88.3%) were euthanized, 5 of 77 (6.5%) died of natural causes, and cause of death was not reported in 4 of 77 (5.2%) cats. Among the 77 cats that died or were euthanized, 56 (72.7%) deaths were attributed to progressive urinary tract neoplasia with 54 of 56 (96.4%) being euthanized and 2 of 56 (3.6%) dying. Seven of 77 (9.1%) deaths were attributed to other disease conditions, whereas the reason for death was unknown in 14 of 77 (18.2%) cats.

Median survival time for all cats was 155 days (95% CI, 110‐222 days). The median survival time was 46 days (95% CI, 8‐82 days) for untreated cats, 176 days (95% CI, 113‐240 days) for cats treated without partial cystectomy, and 294 days (95% CI, 212‐626 days) for cats treated by partial cystectomy with or without other treatments. On unadjusted analysis, survival increased significantly (P < .001) when comparing cats across the ordered treatment groups: no treatment, treatment without partial cystectomy, treatment with partial cystectomy (Figure ​(Figure1).1). Cystectomy (HR, 0.31; 95% CI, 0.17‐0.87) and treatment with NSAIDs (HR, 0.55; 95% CI, 0.33‐0.93) were significantly associated with longer survival times on multivariable analysis. The estimated hazard of death for cats that had both cystectomy and treatment with NSAIDs was significantly decreased (HR, 0.17; 95% CI, 0.08‐0.38) compared to cats that had neither treatment. Age, sex, body weight, duration of clinical signs, serum creatinine concentration, trigonal location, urethral involvement, chemotherapy, radiation therapy, and metastasis at diagnosis were not significantly associated with overall survival. Estimated 1‐ and 2‐year survival rates were 6.7% and 2.2% for untreated cats, 0% and 0% for cats treated without cystectomy, and 28.0% and 8.0% for cats treated with partial cystectomy with or without other treatments, respectively.

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