Transitional cell carcinomas (TCC) of the urinary bladder were diagnosed in four related fishing cats (Prionailurus viverrinus). The major clinical sign in each case was persistent hematuria unresponsive to medical therapy. Cystotomy and biopsy provided an antemortem diagnosis in three of the fishing cats before euthanasia because of progression of clinical signs. The diagnosis was made in the fourth cat after euthanasia because of renal failure. Hematuria improved temporarily in one of the cats diagnosed antemortem and treated with piroxicam and carboplatin. Attempts to isolate a herpesvirus in two of the cats failed. Histopathologic appearance of the TCC was similar to that described for other species. TCC metastasis to the lungs was noted at necropsy in one cat; metastatic disease was not noted in the other fishing cats on gross or histopathologic examination. TCC of the urinary bladder appears to be more prevalent in fishing cats than in other species of domestic or nondomestic felids.
Fishing cats (Prionailurus viverrinus) are small felids native to Southeast Asia and Indonesia and are listed in Appendix II of the Convention on International Trade in Endangered Species.7 Their diet consists of fish, crustaceans, mollusks, frogs, snakes, birds, and small mammals.27 In captivity, they live an average of 10 yr.31 The 2002 Fishing Cat International Studbook lists 286 living captive fishing cats in 80 institutions.33
Transitional cell carcinomas (TCC) are locally infiltrative and invasive tumors. They have been described in older humans, domestic dogs (Canis familaris), domestic cats (Felis catus), sea lions (Zalophus californianus), and beluga whales (Delphinapterus leucas).3,13,24,26,35,37 TCCs are uncommon tumors in the domestic dog and cat.26,37 Hematuria, a commonly reported clinical sign in dogs and cats with TCC, is easily mistaken for a sign of cystitis or other urinary tract related disease.5,19,26,37
A male fishing cat, born at the Rotterdam Zoo in 1984, was relocated to the Cincinnati Zoo in 1985. A medical evaluation was performed in May 1991 because of a 2-wk history of hematuria. Physical examination, abdominal radiographs, complete blood count (CBC), and serum chemistries were unremarkable. The cat was also seronegative for feline immunodeficency virus (FIV), feline leukemia virus (FeLV), feline coronavirus, and toxoplasmosis. A urine sample was not available at the time of this examination. The cat failed to respond to a course of cephalexin (Kelflex®, Dista Products Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA; 25 mg/kg, p.o., b.i.d., for 10 days). Urinalysis performed on a urine sample collected from the cat's enclosure revealed red blood cells (RBCs) (250 cells/μl), white blood cells (WBCs) (2+), and moderate triple phosphate crystals. The cat's diet was changed to a low-Mg, low-P diet (Feline C/D Diet®, Hill's Pet Products, Topeka, Kansas 66601, USA), and enrofloxacin (Baytril®, Miles Inc., Agricultural Division, Shawnee, Kansas 66201, USA; 2.5 mg/kg, p.o., b.i.d., for 14 days) therapy was started. Hematuria resolved initially but recurred intermittently during the next 2.5 yr. Episodes of hematuria were managed with antibiotics and a low-Mg, low-P diet.
A medical evaluation was performed in October 1994 because of an episode of hematuria unresponsive to antibiotic therapy. Physical examination, abdominal radiographs, and serum chemistries were within normal limits. A moderate anemia of 22.6% (reference x = 39.3 ± 5.9)17 was present. A urine sample, obtained through cystocentesis, revealed hematuria (>200 RBCs/HPF) and pyuria (20–40 WBCs/HPF). Urine culture was negative for bacteria. Iron supplementation was started because of the anemia (ferrous sulfate, 162 mg, p.o., s.i.d., for 30 days). Hematuria continued despite treatment with enrofloxacin (2.5 mg/kg, p.o., b.i.d., for 14 days). A double contrast cystogram was performed on a subsequent examination 6 wk later. A mass was suspected in the left ventral bladder wall. Survey radiographs of the thorax were normal at that time. An exploratory laparotomy was performed in November 1994, when the cat's anemia had worsened (hematocrit [Hct] = 12%). Cystotomy revealed a 1-cm-diameter pedunculated mass and several 1- to 3-mm-diameter mural lesions on the left ventral bladder wall. The affected portion of the bladder was resected. TCC of the urinary bladder was diagnosed on biopsy. The mass was noted to be highly malignant and infiltrative. The cat recovered from surgery uneventfully and was returned to the exhibit. No adjunct chemotherapy was administered. Varying degrees of hematuria were observed during the next 6 mo. The cat's condition remained stable until July 1995, when its appetite declined. A caudal abdominal mass was palpable on physical examination, and euthanasia was elected. The Hct at the time of necropsy was 21%. TCC of the urinary bladder with necrosis and metastasis to the lungs were seen grossly and histologically.
An 8-yr-old male fishing cat had macroscopic hematuria in February 1995. The cat had been hand-raised at the San Diego Zoo (SDZ) and had no significant previous medical history. Empirical treatment with antibiotics for presumptive bacterial cystitis did not resolve the hematuria. A physical exam was performed in March 1995. The initial evaluation included a CBC, serum chemistry profile, serology (FIV, FeLV, feline coronavirus, and toxoplasma), abdominal ultrasound, abdominal radiographs, an intravenous pyelogram (IVP), and a double contrast cystogram. The bladder was empty; hence urine was not available for analysis. The only abnormal finding was hyperechoic luminal densities floating in the bladder seen on ultrasound examination after the contrast studies. The Hct at the time was 33.4%. Feline lower urinary tract disease was suspected. The cat was treated with enrofloxacin (5 mg/kg, p.o., b.i.d., for 7 days) and a low-Mg, low-P diet (Hills canned C/D Diet®).
A repeat examination was performed 1 mo later because of continued hematuria. A urethral catheter was passed with some difficulty to obtain a urine sample for urinalysis and bacterial culture. A percutaneous needle biopsy of the kidney was performed for histologic evaluation. The Hct had declined to 28.7%. The cat was released back to the exhibit pending results of diagnostic testing. Heavy amorphous debris in the urine interfered with the sediment analysis. Two colonies of Proteus mirabilis and one colony of Escherichia coli were isolated from urine culture. The renal biopsy was normal. One week later, the cat presented with acute onset lethargy. Significant hematology results included a mild left shift of 3% band neutrophils (reference x = 0.183 ± 0.128 × 103 cells/μl)17 and a mild azotemia (blood urea nitrogen [BUN] = 14.9 mmol/L [42 mg/dl]; reference x = 12.5 ± 2.14 mmol/L).17 Although the bladder was not distended, it was thought the cat had intermittent urethral obstruction. The bladder wall was thickened (0.5 cm) on ultrasound examination. The cat received i.v. and s.c. fluid therapy. Repeat urinalysis revealed hematuria, pyuria, and intracellular bacteria as well as increased number of epithelial cell rafts. Antibiotic therapy was started with ceftiofur (Naxel®, Upjohn Company, Animal Health Division, Kalamazoo, Michigan 49001, USA; 4 mg/kg, i.m., s.i.d., for 7 days). Hematuria persisted, and after 7 days, antibiotic therapy was changed to enrofloxacin (6 mg/kg, p.o. or i.m., s.i.d., for 7 days). Another examination was performed 8 days later for an urethrogram and a repeat cystogram. Radiographs revealed a pneumoperitoneum, so an abdominal exploratory was performed. Gastric perforation with secondary peritonitis was discovered. Abnormalities associated with the kidneys, ureters, or urinary bladder were not evident grossly; however, a cystotomy was not performed. Histologic examination of gastric tissue collected at surgery revealed severe, chronic pyogranulomatous gastritis with associated foreign material. The cat required intensive care for 1 wk after surgery, and its condition gradually improved; however, the hematuria persisted. The Hct was 21–30% during this period. In June, amitriptyline (Elavil®, Stuart Pharmaceuticals, Wilmington, Delaware 19897, USA; 5 mg, p.o., s.i.d.) was started to treat for presumptive interstitial cystitis.6 Urine collected through cystocentesis cultured negative for bacteria. Macroscopic hematuria continued on an intermittent basis. The amitriptyline dose was increased to 5 mg administered, p.o., b.i.d., 2 wk later.
In August, the cat was observed to have stranguria and was acutely depressed. An enlarged bladder was palpable on exam. A CBC revealed a leukocytosis of 34 × 103 WBCs/μl (reference x = 8.410 × 103 cells/μl)17 and left shift of 6% band neutrophils. The Hct was 31%. Serum chemistries revealed severe azotemia with a BUN of 69.6 mmol/L (195 mg/dl) and a creatinine of 1,264 μM/ L (14.3 mg/dl; reference x = 177 ± 35 μM/L).17 Urine collected through cystocentesis was negative for ureaplasms and viruses as well as bacteria. A cystogram performed at the time was normal. An indwelling urinary catheter was placed, and therapy with i.v. fluids and cefotaxime (Claphoran®, Aventis Pharamaceuticals, Bridgewater, New Jersey 08807, USA; 50 mg/kg, i.v., b.i.d.) was initiated. Renal failure secondary to urinary obstruction was diagnosed. Euthanasia was performed because of a lack of response to therapy. The Hct at the time of euthanasia was 24%.
At necropsy, the wall of the apex and body of the urinary bladder was 0.2–0.3 cm thick, and there was multifocal ulceration, with petechial and ecchymotic hemorrhage. A 1.5-cm area of the mucosa and wall of the urinary bladder, extending circumferentially from the neck to the left ureterovesicular junction, was 0.8 cm thick, firm, tan, and irregular (Fig. 1). This had caused obstruction of the left ureter resulting in hydroureter and hydronephrosis. Histopathology revealed TCC in the neck of the urinary bladder composed of a transmural proliferation of pleomorphic polygonal cells, which infiltrated and separated connective tissue and smooth muscle fasciculi. Neoplastic cells had pleomorphic hypochromatic nuclei with prominent nucleoli and were arranged in irregular cords and acinar structures, with occasional central individual cell necrosis. There were three mitotic figures per ×40 field on average. There was no evidence that the TCC had caused lymphatic invasion or distant metastases.
An 11-yr-old female fishing cat living at the SDZ was examined in August 1995 because of hematuria of 2-mo duration. This female had been imported from the Rotterdam Zoo in 1986 and had given birth in 1987 to the animal described in case 2. Previous medical history was unremarkable. The initial examination included CBC, serum chemistry profile, serology (FIV, FeLV, feline coronavirus, and toxoplasma), abdominal ultrasound, abdominal radiographs, urine collection through cystocentesis for urinalysis, bacterial and viral culture, IVP, double contrast cystogram, and renal biopsy. A mild anemia of 26.6% was present (reference x = 37.0 ± 8.8).17 The urine contained RBCs too numerous to count. Abnormalities were not seen on the IVP or double contrast cystogram; however, a possible mass effect was noted on ultrasound of the bladder. Urine culture was negative for aerobic organisms as well as ureaplasms; however, Herpes simplex virus was isolated. The renal biopsy, serum chemistries, and serology were normal.
Abdominal exploratory surgery and cystotomy were performed. A 6-mm-diameter reddened mass protruding from the left ventral bladder mucosa was present. The bladder mucosa had a pronounced cobblestone appearance. Full thickness resection of the bladder wall mass was performed, and the tissue was submitted for histologic examination. Bladder tissue, as well as urine, was submitted for repeat ureaplasm and viral culture. No organisms were isolated. From the specimen collected at surgery, there was a broad-based, exophytic, botryoid mass (0.8 × 0.8 × 0.6 cm) that protruded from the mucosa of the urinary bladder. Histologically, the mass was biphasic. Some areas were exophytic and composed of sheets of neoplastic polygonal cells (Fig. 2). Other areas were endophytic with neoplastic cells arranged in nests, irregular cords, and acinar structures. Throughout the neoplasm, the cells had moderate nuclear pleomorphism with an average of four mitotic figures per ×40 field, many of which were atypical. There were no neoplastic cells at the margins of the biopsy; however, multiple areas of the remaining mucosa were hyperplastic or dysplastic or both. TCC was diagnosed.
A follow-up examination was performed 3 wk after surgery. Evidence of metastatic disease was not present on thoracic radiographs. Hematuria was still evident; however, the Hct had increased to 31%. Chemotherapy for TCC using piroxicam (Feldene®, Pfizer, Inc., U.S. Animal Health Operations, New York, New York 10017, USA; 0.3 mg/kg, p.o., every 3 days) was started in September 1995 and continued until mid-January 1996. One month after starting piroxicam, treatment with carboplatin (Paraplatin®, Bristol Laboratories, Oncology Products, Bristol-Myers Squibb Co., Princeton, New Jersey 08543, USA; 175 mg/m2 in 100 ml NaCl, i.v., for 30 min) was instituted. A total of four treatments were administered every 3 wk for 3 mo. Because infertility would result from carboplatin therapy, procedures to stimulate ovaries and harvest oocytes surgically were performed before the initiation of carboplatin therapy. Hematology and serum chemistry profiles were monitored for signs of myelosuppression or nephrotoxicity (or both) secondary to the chemotherapy. During this period, the Hct was 26–31%. WBC counts and cell differentials remained stable, as did the renal parameters.
Urine was monitored on the basis of gross appearance and opportunistic urinalyses performed on urine collected through cystocentesis or urethral catheterization during chemotherapy treatments. Macroscopic hematuria resolved 1 mo after the piroxicam was started; however, microscopic hematuria was still evident. Urinalyses obtained through cystocentesis during the period of carboplatin therapy revealed varying amounts of blood on the basis of urine dipsticks (50–250 RBCs/μl); however, erythrocytes were not present on urine sediment examination except on the last and 2 wk after carboplatin treatment. In March 1996, 2 mo after carboplatin therapy and 6 wk after the piroxicam was discontinued gross hematuria was observed. Eight weeks after completion of piroxicam, it was reinstated at the original dose and continued until September 1996. Cystoscopy, performed in April 1996, using a 2.7 mm rigid endoscope (Karl Storz Veterinary Endoscopy, Goleta, California 93117, USA) without the cannula revealed mucosal irregularity and hemorrhage in the left bladder wall consistent with the previous bladder mass resection site. There was also a diffuse erythematous area on the right side of the bladder. During the next 4 mo, variable amounts of blood (0 to 250 RBCs/μl) were present in the urine obtained through catheterization, cystocentesis, or collected from the den floor. Erythrocytes were not present on sediment examination until September. Follow-up cystoscopy performed in August revealed one focal area of hemorrhage and increased flocculent debris. Repeat cystoscopy evaluation 1 mo later revealed increased hemorrhage from the bladder wall. The disease appeared to be progressive, and euthanasia was performed in October 1996. The Hct at the time of euthanasia was 31%.
At necropsy, the wall of the urinary bladder was 0.2–0.3 cm thick with multifocal ulceration and ecchymotic hemorrhage. In the mucosa, 1.5 cm cranial to the trigone, there was a 0.1-cm diameter, firm, tan-brown sessile mass. Histologically, the necropsy sections of the TCC and surrounding mucosa from the urinary bladder were similar to the endophytic areas of the biopsy specimen; however, there was invasion of the lamina propria and submucosa by neoplastic cells arranged in acinar structures and surrounded by moderate numbers of lymphocytes, plasma cells, and neutrophils. There was no evidence that the TCC had invaded lymphatics or metastasized.
A 1-yr-old male fishing cat was brought into the SDZ collection in 1994 from another U.S. zoologic institution. Medical history was unremarkable until August 2000, when the cat was examined because of a 2-wk history of hematuria. Initial diagnostic testing included CBC, chemistry panel, serology (FIV, FeLV, feline coronavirus, toxoplasma), urinalysis, survey abdominal radiographs, double contrast cystography, and ultrasound. A double contrast cystogram revealed a suspicious area in the trigone region, although a mass was not evident on ultrasound. Results of CBC, chemistry panel, and serology were within normal limits. The Hct was 39%. A urine sample obtained through cystocentesis revealed a large number of RBCs. Bacterial culture of the urine was negative. Because of the abnormal cystogram and the history of TCC in other fishing cats, an exploratory laparotomy was performed. Intraoperative cystoscopy was performed to better assess the trigone region of the bladder. A 2.7 mm rigid endoscope (Karl Storz) was inserted through a stab incision made in the ventral bladder wall. Sterile normal saline was instilled into the bladder through the endoscope cannula to facilitate observation. A discrete mass was not evident; however, the bladder mucosa in the area of the trigone was irregular and hemorrhagic. Biopsy specimens were collected using a biopsy forceps inserted through the biopsy channel of the endoscope cannula. The cat recovered uneventfully from surgery. Biopsy results confirmed TCC of the urinary bladder. The cat was treated with piroxicam (0.3 mg/ kg, p.o., every other day) as a palliative measure. Grossly observed hematuria was intermittent initially and became persistent in mid-October 2000. Euthanasia was performed in December 2000 because of clinical deterioration. The cat was anemic (Hct = 12%) and azotemic (BUN = 30.7 mmol/L [86 mg/dl]) at the time.
At necropsy, TCC of the wall of the urinary bladder with local invasion and intralumenal hemorrhage was present. Histologically, the tumor contained a monomorphic population of pleomorphic, polygonal, basophilic epithelial cells, with numerous mast cells seen admixed with the tumor cells. Evidence of vascular invasion or metastasis was not seen. Evidence of renal disease was not present.
Polymerase chain reaction
Approximately 100 μm of formalin-fixed, paraffin-embedded urinary bladder, with and without tumor, from cases 2 and 3 was examined for herpesvirus deoxyribonucleic acid (DNA) sequences using polymerase chain reaction (PCR). From each sample, DNA was extracted and subjected to nested, consensus primer PCR reactions designed to amplify short regions of DNA polymerase and terminase or DNA packaging protein.15,40 These two highly conserved genes are found in all herpesviruses. No amplified DNA products for the terminase or DNA packaging protein was detected in either cat from either tumor or nontumor bladder tissue. However, weak bands of the expected size were obtained in the terminase reaction for case 1 nontumor and case 2 tumor. Insufficient amounts of PCR product were obtained to carry out DNA sequencing. Approximately 100 μm of formalin-fixed, paraffin-embedded urinary bladder, with and without tumor from case 2 and case 3 was also examined for feline herpesvirus-1 DNA sequences using PCR.41 All samples were negative.
Neoplasia involving the urinary bladder of domestic felids is rare.3,37 Studies have estimated occurrence rate of urinary bladder neoplasia at 0.07– 0.38% in domestic cats.11,42 In one study evaluating 3,145 feline necropsies, only two carcinomas of the urinary bladder were found.29 In another study in the domestic cat, eight of 27 (30%) cases of urinary bladder tumors during 10 yr were TCC.37 In that series of cases, males outnumbered females almost three to one. Another study reported TCC in cats to be more common in females.5 In the current report, three males and one female were affected. In one study evaluating TCC in domestic dogs, females outnumbered males 1.7:1.19 The mean age of cats with urinary bladder neoplasms has been reported to be 8.1–11.6 yr, whereas the mean age of fishing cats in this report was 9 yr.5,37,42
Hematuria is the most common clinical sign of bladder neoplasia in domestic cats,37 domestic dogs, and humans.4,10 Pyuria, proteinuria, and bacteriuria are also commonly seen in dogs and cats with urinary bladder neoplasms.4,26,37 Hematuria was the presenting problem in all four cats in the current report. Proteinuria, pyuria, and bacteriuria were seen to varying degrees, although significant hematuria was the predominant finding on urinalysis. Blood loss from hematuria resulted in varying degrees of anemia in the fishing cats. Anemia (packed cell volume < 25) was noted in five of 20 cats in a review of feline TCC.37 Two of the four affected fishing cats were anemic before or at the diagnosis of TCC of the urinary bladder. All four developed anemia at some time during the course of the disease.
A diagnosis of TCC was made antemortem in three cases and postmortem in one case. The cat in case 2, diagnosed postmortem, was initially thought to have idiopathic feline lower urinary tract disease. The episode of gastric perforation and peritonitis confounded the clinical picture shifting emphasis temporarily away from the hematuria. The cat was not uremic, when the gastric perforation was diagnosed, but it did have an episode of mild azotemia earlier in the month. This may have predisposed to gastric ulceration and subsequent perforation. Stress secondary to manipulations may have also contributed to gastric ulceration. Retrospective review of the cystogram performed in August 1995 revealed a suspicious area in the trigone region that had been overlooked. This likely was the area of the TCC. A double contrast cystogram may have better delineated the lesion.
Multiple diagnostic modalities were used in these cases. Contrast radiography and ultrasonography were useful, but cystotomy and biopsy produced the most definitive diagnoses. It was difficult on some occasions to obtain diagnostic quality contrast studies. Ultrasound examinations were performed in cases 2, 3, and 4. A thickened bladder wall was seen on ultrasound in case 2. Limitations in resolution of the ultrasound machine in use at the time prevented a detailed evaluation of the trigone region. A mass was suspected from the ultrasound examination in case 3. Although not performed, ultrasound-guided fine-needle aspirates of suspected urinary bladder masses might have assisted with the diagnosis. The absence of significant ultrasound abnormalities in case 4 is not surprising given the lack of a discrete mass at surgery. The degree of distension will determine how well bladder wall irregularities and masses can be detected with ultrasonography. Catheterization and instilling sterile saline solution may facilitate bladder wall observation in cases where the bladder is only minimally distended. Cystoscopy in the female cat was useful in evaluation of and monitoring the bladder mucosa. Urethral size limitations prevented a cannula with a biopsy channel being used for the cystoscopy; therefore it was not possible to obtain biopsy samples. A small diameter endoscope was not available to evaluate the male cats through cystoscopy.
A veterinary bladder tumor antigen test (VBTA Test, Alidex Inc., a subsididary of Polymedco Inc., Redmond, Washington 98052, USA) has been evaluated as a screening test in dogs with urinary bladder TCC.16 Dogs with confirmed TCC as well as dogs with non-TCC urinary tract disease were evaluated. The sensitivity of the test was 88% and the specificity was 84–87% for healthy or unhealthy dogs without urinary tract disease. However, the specificity for dogs with non-TCC urinary tract disease was 41%, making false positives a problem. That study suggested that the probability of detecting TCC using this test in a targeted population, with a higher prevalence of the disease, would be improved. This test has not been evaluated in cats and is likely to have similar limitations but still warrants consideration in developing diagnostic strategies for fishing cats.
Chemotherapy was attempted in case 3. Piroxicam, a nonsteroidal anti-inflammatory thought to have some antitumoricidal activity, has been used in the treatment of canine bladder neoplasia.20 Canine TCC have increased cyclooxyenase-2 (Cox) expression.18 Piroxicam, a Cox-1 and Cox-2 inhibitor acts to suppress Cox-2 activity, which reduces prostaglandin E2 (PGE2). PGE2-mediated immunosuppression is thought to play a role in the pathogenesis of canine TCC.20 Piroxicam is recommended for daily use in the domestic dog. A dosing schedule of one treatment every 3 days was chosen for this case because of increased sensitivity of felines to anti-inflammatory drugs. The cat might have tolerated more frequent dosing, which may have improved clinical response. The cat in case 4 was treated with piroxicam every other day with little evidence of benefit. That cat was azotemic when euthanized, but no evidence of renal disease was present histologically. This may have represented a prerenal azotemia or have been too early in the process of renal disease for histologic changes to be present.
Carboplatin has been evaluated as an alternative to cisplatin in the treatment of feline neoplasia because of reduced toxicity.43 Cisplatin often causes fatal pulmonary edema in domestic cats.21 Although carboplatin can cause myelosuppression, both carboplatin and piroxicam can be potentially nephrotoxic. The cat in case 3 tolerated both the carboplatin and piroxicam. Although complete remission did not occur, the chemotherapy may have been responsible for temporary improvement in the hematuria. It is likely that improvement was because of the combination therapy. In dogs with TCC, median survival time was increased when combination protocols were used as compared with single agent therapy.34 Platinum chemotherapeutic agents are most effective when the maximal dose with the minimum amount of toxicity is used.43 A study in 1997 reported domestic cats to tolerate a single i.v. dose of 200 mg/m2 carboplatin.14 It is possible that a higher dosage or longer treatment would have been tolerated by this cat and would have resulted in resolution of clinical signs for a longer period.
More research on the treatment of canine TCC has been conducted during the past several years. Gemcitabine (Gemzar®, Eli Lilly and Company, Indianapolis, Indiana 46285, USA), a novel nucleoside analogue, has promising antitumor activity in people and is currently undergoing evaluation in domestic dogs.23 Deracoxib (Deramaxx®, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936, USA), a selective Cox-2 inhibitor has shown promise for delaying tumor development in domestic dogs with TCC.1,2 Concurrent chemotherapy and radiation therapy may also have some benefit in the treatment of canine TCC.36 Photodynamic therapy using 5-aminolevulinic acid may prove to have some benefit for intravesicular treatment.32 Surgical debulking, when combined with chemotherapy, prolonged median survival time in one study.19 These treatment modalities may prove useful in the treatment of future cases of TCC in fishing cats.
The gross and histopathologic features of the TCCs in the fishing cats described in this study are similar to reports in other species. TCCs are often at the neck or trigone of the urinary bladder, tend to be multifocal, and may have epithelial abnormalities ranging from hyperplasia to in-situ carcinoma in uroepithelium adjacent to the invasive lesion.25,35,39 Two cats had lesions involving the neck– trigone regions of the bladder, and two cats had lesions involving the ventral bladder wall. In dogs and humans, 50% of TCC will have late metastasis to regional lymph nodes and lungs; peritoneal implantation or retrograde lymphatic spread to tissues in the hind limbs is also common.25,35 One case in this series had evidence of metastasis.
Domestic cats are prone to lower urinary tract disease, which has been associated with multiple factors including a herpesvirus.22 A herpesvirus association with the cystitis and TCCs in two of the fishing cats in this study was not proven. Urine from the cat in case 2 was culture negative for viruses. The Herpes simplex virus isolated from urine in case 3 was probably a contaminant because no herpes virus was isolated from bladder or urine collected at the time of the cystotomy, and the analysis had been done at a human hospital. Evaluation of urinary bladder tissue collected at necropsy also failed to reveal a herpes virus through PCR analysis. It is possible that either a herpesvirus was present in neoplastic and nonneoplastic urinary bladder of both animals but not in large amounts or that the virus was no longer present when the samples were collected. The significance of the weak bands for the herpes virus terminase protein DNA is unclear.
Factors that have been associated with TCCs in humans as well as animals include exposure carcinogenic chemicals such as 2-napthylamine, benzidine, and 4-aminobiphenyl, cyclophosphamide metabolites such as acrolein, cigarette smoke, bracken fern, viruses, parasites or any combination of these agents.3,9,25,30,35,37,39 One etiology that has been described for TCC is exposure of bladder epithelium to tryptophan metabolites such as o-aminophenol.28,38 Domestic cats have a lower prevalence of urinary bladder neoplasia compared with dogs and humans and excrete very low quantities of o-aminophenol.3,37 It would have been interesting to analyze samples of urine from the two fishing cats in this case report for o-aminophenol, and if they had high levels, possibly correlate this to the TCC. Unfortunately urine was not available from either cat. A urine sample from an unrelated normal 5-yr-old male fishing cat was collected from the concrete floor of its enclosure. Urine volatiles were sampled using gas chromatograph–mass spectrometer analyses. None of the isomers (o-, m-, or p-) of aminophenol were present. A detailed search for o-aminophenol (o-toluidine, relative retention time 0.990) also was negative (Hagey, unpubl. data). The fact that no o-aminophenol was detected in this urine sample suggests that similar to domestic cats, fishing cats may also excrete low levels of this compound.
Chronic inflammation has been implicated as a cause of neoplasia and has been associated with the development specifically of urinary bladder neoplasia.30 It is possible that chronic inflammation secondary to bacterial cystitis or feline lower urinary tract disease leads to TCC in these cats. In case 1, hematuria was noted 4 yr before and occurred intermittently until the time of diagnosis. It is not known where along this timeframe TCC actually developed in the bladder.
Dye manufacturers, painters, farmers, rubber workers, electrical workers, pesticide applicators, and petroleum or chemical industry workers have increased risk for bladder cancer.8 In an epidemiology study evaluating household dogs, researchers found correlations with obesity, exposure to flea or tick (or both) dips and to marshes sprayed for mosquitoes to increased risk of developing bladder cancer.12 Inert ingredients in the insecticides are potential carcinogens, and these compounds may be stored in adipose tissue for prolonged periods increasing exposure time.12 Sixty-six of 370 California sea lion strandings along the California coast from 1979–1994 had urinary cancer of probable transitional cell origin.13 One possible explanation for the high number of cases was exposure to environmental contaminants in the ocean. The female in case 3 was one of the first cats to inhabit the zoo's new fishing cat exhibit and lived there for 8 yr. The male in case 2 lived in the same exhibit for 7 yr. The male in case 4 had lived in the exhibit for 6 yr. Except for one female still living in this exhibit, these three animals had been housed the longest of any fishing cats in the SDZ collection. It is interesting that TCC was diagnosed in case 2 and 3 within 1 yr. It is tempting to speculate that these cats had been exposed to a potential carcinogen in their environment; however, a survey for toxins in their environment was not conducted.
The only report regarding risk factors for TCC associated with diet involves sea lions.13 Piscivorous sea lions may concentrate environmental toxins because fish accumulate toxins in their tissues.13 The diet for the SDZ fishing cats at the time consisted of commercial feline kibble and meat-based diets, mice, carp, and trout. Carp and trout would be the only diet items unique to fishing cats versus other felids in the collection, and it is not known if chemical contaminants present in the fish contributed to the development of bladder neoplasia. A contrasting dietary perspective considers the proposed benefits of omega-3 fatty acids found in fish in reducing the risk of cancer. One could speculate that a species adapted to a fish-based diet consumes higher levels of beneficial fatty acids in the wild. It is unknown if captive fishing cat diets provide insufficient levels of fatty acids thereby increasing the risk of neoplasia; however, one would expect an increase in all types of cancer in captive fishing cats.
The pedigrees of all four fishing cats, representing three generations, are shown in Figure 3. The lineages of these four individuals can be traced to a common sire and two common dams, all captive born and housed at the Rotterdam Zoo. In the fishing cat Species Survival Plan population, the overall level of inbreeding (mean F values = 0.186) is relatively high (Swanson, pers. comm.). Inheritance has not been reported to affect TCC occurrence in domestic felids or canids, although Scottish Terriers may be predisposed.19 In humans, several genes (GSTM1, NAT1, and NAT2), oncogenes (H-ras, c-myc, and erb-B-2) and tumor suppressor genes (Rb and p53) have been associated with an increased incidence of urinary bladder neoplasia.30,35 Genetics may have played a role in the development of TCC in the fishing cats described here.
Since 1986, six fishing cats >5 yr of age have lived at the SDZ. All six cats had clinical presentations; three for hematuria and three for other problems. Of these six cats, two died without evidence of urinary bladder disease, three represent the cases presented here, and one remained in the collection in 2004. The clinical prevalence for TCC in the SDZ collection is 50% for cats >5 yr of age during 1984–2003. Since 1985, five fishing cats >5 yr of age have died. Three of these five had TCC, making the necropsy prevalence for this period 60%.
SDZ necropsy records from 1983 to 2000 contain two additional cases of TCC in carnivores, a golden cat (Felis temnincki) diagnosed in 1985 and an Amur leopard cat (Prionailuris bengalensis euptilura) diagnosed in 1998. The Felid Taxon Advisory Group pathologist considers TCC of the urinary bladder in exotic felids to be rare (Munson, pers. comm.). Disseminated urinary bladder neoplasia was seen in one fishing cat in 1989 at the Rotterdam Zoo, although histology is not available (Schaftenaar, pers. comm.). Four additional cases of TCC have been diagnosed in fishing cats in U.S. institutions within the past 3 yr (Reavill, Cole, Rasmussen, and Douglass, pers. comm.) and two cases have been diagnosed in Australia (Lynch, pers. comm.). These six new cases and the four in this study represent six males and four females with an average age of 10.3 years.
The reason for the high prevalence of TCC in fishing cats is unknown but warrants further investigation. As with domestic dogs and cats, urinary tract neoplasia should be suspected in cases of persistent hematuria unresponsive to medical therapy. The authors recommend monitoring fishing cats >6–7 yr of age for hematuria, with cystoscopy or cystotomy after any observed hematuria.
We thank Dr. Richard Garber of Pathogenesis Corporation, Seattle, Washington, for performing the PCR tests for herpesviruses and Dr. Lee Hagey, Center for Reproduction of Endangered Species, San Diego Zoo, San Diego, California, for performing the gas chromatography analysis on fishing cat urine. We also acknowledge Dr. Greg Ogilvie, College of Veterinary Medicine, Colorado State University, Fort Collins, Colorado, and Dr. Keith Richter, Veterinary Specialty Hospital of San Diego, Rancho Santa Fe, California, for advice with the chemotherapy protocols. Dr. Richter also provided valuable input during the preparation of this manuscript. We thank Dr. Bill Swanson, Cincinnati Zoo, Cincinnati, Ohio, and Lynda Roberts, Riverbanks Zoo, Columbia, South Carolina, for help with the studbook information.