Transitional cell carcinoma of the urinary bladder in a 12-year-oldBelgian Warmblood geldingZ. M. Lisowski*, T. S. Mair and D. Fews†
Bell Equine Veterinary Clinic, Mereworth, Kent; and †School of Veterinary Science, University of Bristol, UK.*Corresponding author email: [email protected]
SummaryA 12-year-old Belgian Warmblood gelding was examined forhaematuria and dysuria of 24 h duration. Cystoscopy revealedan intraluminal multinodular soft tissue mass originating fromthe dorsal bladder neck. Histopathological examination ofbiopsies identified transitional cell carcinoma. The bladdermass was surgically debulked via a temporary perinealurethrotomy. The horse commenced treatment with oralpiroxicam. Follow-up examination 18 months post operativelyrevealed no evidence of tumour recurrence. Neoplasia ofthe equine bladder is uncommon and this case describesthe successful short-term outcome of treatment of atransitional cell carcinoma by surgical debulking and oralpiroxicam.
IntroductionPrimary neoplasia of the equine urinary bladder is rare. Themost commonly reported neoplasm of the bladder in thehorse is squamous cell carcinoma (SCC) (Fischer et al. 1985;Gandini et al. 1998; Serena et al. 2009). Whilst transitional cellcarcinoma (TCC) is the most frequently reported primarybladder neoplasm in the dog (Mutsaers et al. 2003) and man(Johansson and Cohen 1997), it has rarely been reported in thehorse with only 5 previously published cases (Traub et al. 1983;Fischer et al. 1985; Servantie et al. 1986; Turner et al. 1995;Patterson-Kane et al. 2000). Other reports of neoplasia of thehorse bladder include lymphosarcoma, leiomyosarcoma,fibromatous polyp and rhabdomyosarcoma (Sweeney et al.1991; Turnquist et al. 1993; Hurcombe et al. 2008; Barrell andHendrickson 2009; Waldridge 2010).
There are few reports of attempted treatment of bladderneoplasia in horses and in most recorded cases the affectedhorses were subjected to euthanasia. Chemotherapy withdoxorubicin and dexamethasone was unsuccessful in treatinga poorly differentiated leiomyosarcoma of the bladder in amare reported by Hurcombe et al. (2008). Failed attempts tosurgically excise a rhabdomyosarcoma and a SCC have alsobeen previously described (Turnquist et al. 1993; Gandini et al.1998). Monthly manual debulking and 5-fluorouracil instillationwas anecdotally reported to be effective in one mare withSCC of the bladder (Cornelisse 2003) and resection cystoplastyfollowed by oral piroxicam therapy was effective (norecurrence within 6 months) in another mare with SCC of thebladder described by Serena et al. (2009). This report describesthe successful short-term management of a TCC in thebladder of an adult gelding by surgical debulking and oralpiroxicam.
Case details
Case historyA 12-year-old Belgian Warmblood gelding was examined for a24 h history of stranguria and haematuria. The owner reportedthat the horse had had no previous problems with urination.
Clinical findings and investigationOn examination the horse was bright, alert and responsive.All clinical parameters were within normal limits. Rectalexamination revealed a partially full bladder with no palpablecalculi. At the bladder neck an area of thickened softtissue was palpable. Transrectal ultrasonography showedhyperechoic urine within the bladder and an ill-definedcircular structure on the dorsal bladder wall on the left handside. The left ureter appeared thickened, but the kidneyappeared normal with no evidence of hydronephrosisindicating obstruction. The horse was sedated (500 mgxylazine i.v. and 10 mg butorphanol i.v.) and a urinary catheterwas passed which yielded thick sabulous urine. The bladderfailed to empty normally and was irrigated with 0.9% saline toremove the remaining sediment. Urinanalysis revealedhaematuria, proteinuria and pyuria. Moderate amounts ofepithelial cells, erythrocytes and bacteria were seen on urinecytology. Bacterial culture yielded no growth. Haematologyand serum biochemistry profiles were within normal limits.
Cystoscopy revealed an intraluminal multinodular softtissue mass originating from the left dorsal bladder neck (Fig 1).The left ureteral opening was obscured by the mass but urinewas seen exiting the opening. The right ureteral openingappeared grossly normal. Multiple mucosal pinch biopsies ofthe mass were obtained via the endoscope. Histopathologicalexamination of the biopsies revealed areas of neoplasticchange consistent with TCC.
Standing radiography of the thorax showed noabnormalities of the lungs. A routine standing laparoscopicexamination was performed to visualise the serosal surfaceof the bladder and assess the peritoneal cavity for anymetastases. Prior to surgery the horse was administeredphenylbutazone (4.4 mg/kg bwt i.v.), benzylpenicillin sodium(10 mg/kg bwt i.v.) and gentamicin sulfate (6.6 mg/kgbwt i.v.). The horse was sedated with 6 mg detomidinehydrochloride i.v. and 10 mg butorphanol i.v. Sedation wasmaintained throughout the laparoscopy via i.v. detomodineinfusion administered to effect. Xylazine (0.22 mg/kg bwt) andlidocaine (0.35 mg/kg bwt) were administered epidurally in a12 ml total volume of sterile saline. Routine exploratorylaparoscopy via the left paralumbar fossa did not reveal anyevidence of further masses, although the serosal surface of the
caudal bladder wall was mildly oedematous and discoloured,with oedema of the lateral ligament.
TreatmentFollowing completion of the laparoscopic examination androutine closure of the laparoscopic portals, a 5 cm temporaryperineal urethrotomy was performed. A flexible endoscopewas passed through the urethrotomy to visualise the massat the bladder neck. The mass was surgically debulkedwith laparoscopy scissors and Babcock forceps via theurethrotomy. Mild haemorrhage from the excision site wasobserved. Samples of the mass were fixed in 10% formal salineand sent for histological examination. The urethrotomy wasallowed to heal by secondary intention. Post operatively, thehorse received gentamicin sulfate (6.6 mg/kg bwt i.v. q. 24 h)for 3 days, benzylpenicillin sodium (10 mg/kg bwt i.v. q. 8 h)and meloxicam (0.6 mg/kg bwt per os q. 24 h) for 5 days. OnDay 6 the horse commenced oral potentiated sulfonamides(25 mg sulfadiazine and 5 mg trimethoprim/kg bwt per os q.24 h) for 7 days.
Repeat cystoscopy performed 24 h after surgicaldebulking revealed a small mass of abnormal tissue remainingat the surgical site (Fig 2). The ureteral opening was visible andurine was seen exiting the opening. Over the next 5 days, thehorse remained bright, alert and responsive with only a fewepisodes of dysuria. Small amounts of haemorrhage were seenduring urination for up to 3 days post operatively. The horsewas discharged from the hospital 5 days after surgery. Theurethrotomy and laparoscopy portals healed with nocomplications. Treatment with piroxicam (0.2 mg/kg bwt peros q. 24 h) was commenced 10 days post operatively andpiroxicam continued at this dose for 4 months and thenreduced to 0.1 mg/kg bwt per os q. 24 h.
OutcomeThe horse was re-examined at the clinic 3 days followingdischarge from the hospital after the owner was concerned
that he had become dysuric. Cystoscopy revealed mildinflammation within the bladder but the site of tumourexcision was similar to its appearance 24 h after the surgery.The horse commenced oral phenylbutazone (2.2 mg/kg bwtper os q. 12 h) for 5 days.
At 4 weeks post surgery the horse was re-examined. Rectalpalpation was unremarkable and cystoscopy showed a small,smooth swelling close to the left ureteral ostium. Mucosal pinchbiopsies obtained via the endoscope showed the presence ofurothelium with extensive vacuolation, glandular metaplasia,and chronic inflammation; there was no evidence ofneoplastic change.
Further follow-up examinations 4, 11 and 18 months postoperatively revealed no abnormalities on cystoscopy apartfrom mild thickening around the left ureteral opening (Fig 2).Thirty months after treatment, the owner reported norecurrence of haematuria but had observed one episode ofself-resolving dysuria approximately 9 months after treatment.
HistopathologyThe mass was submitted as 4 pieces of tissue, ranging from1.7 ¥ 1.7 ¥ 1 to 5 ¥ 2.5 ¥ 1.5 cm in size. Areas of the surfacewere roughened and the samples were grossly opaque, greyand gelatinous. Routine histological examination identifiedportions of a polypoid lesion, with an oedematous, inflamedstroma, populated by plump spindle to stellate-shaped cellswith foci of mature fibrous tissue and areas of granulation tissueformation. The surface epithelium was frequently separatingwith foci of ulceration. The remaining surface epitheliumwas hyperplastic or dysplastic, with foci of neoplastictransformation showing loss of definition of the basal cell layerand/or infiltration of the underlying stroma (Fig 3). There wasalso extensive intestinal epithelial differentiation (intestinalmetaplasia), present either as a single layer of cells, or as asurface layer covering several layers of squamous epithelial
Fig 1: Endoscopic view of the intraluminal mass on the dorsalbladder wall.
Fig 2: Endoscopic view of the bladder wall 4 weeks post surgery.Note the smooth protrusion of the ureteral opening.
2 Transitional cell carcinoma of the urinary bladder in a Warmblood gelding
cells (Figs 4 and 5). Islands of poorly differentiated squamousand glandular epithelial cells were present within the stroma,deep to the surface epithelial layer (Fig 6). The overallhistopathological appearance was of a polypoid lesion with arange of changes present within the epithelial componentincluding TCC, carcinoma in situ, Brunn’s nest formation,glandular metaplasia, intestinal metaplasia and transitionalcell hyperplasia and dysplasia.
Immunohistochemistry was also performed and revealednumerous cyclooxygenase-2 (COX-2) positive atypicalepithelial cells that exfoliated and invaded the superficialstroma within multiple fragments of the tissue. This indicatedthe potential value of COX-inhibitors as a potential treatment.
A final diagnosis of TCC was made.
DiscussionTransitional cell carcinoma has been rarely reported in theequine bladder with no previously published reports of
successful treatment of TCC in the horse. The combination ofsurgical debulking and oral piroxicam appeared to besuccessful in this case, although the relative efficacy of these 2different treatments in achieving resolution of the tumour isimpossible to establish. Piroxicam is commonly used incombination with chemotherapy to treat TCC in dogs (Henry2003) and selective cyclooxygenase-2 (COX-2) inhibitors, suchas celecoxib, have also been used as part of multimodaltherapy for treating urothelial cell carcinoma in people(Dovedi and Davies 2009). The apparent remission of thetumour and healing of the surgical site despite the presence ofa residual mass after surgical debulking is, however, suggestivethat piroxicam helped to resolve the disease.
The urinary tract is lined by transitional cells that extendfrom the renal pelvis to the ureters, bladder and urethra andadditionally includes the prostatic ducts and prostatic urethrain males. Transitional cell carcinoma may arise from any part ofthe urinary tract but, in horses, they have been most frequentlyreported in the bladder wall (Traub et al. 1983; Fischer et al.
100 µm
Fig 3: Bladder mucosa. Transitional cell hyperplasia and dysplasia,with frequent intracellular oedema and islands of neoplasticepithelial cells present deep to the basement membrane, within anoedematous, inflamed stroma.
100 µm
Fig 4: Bladder mucosa. Intestinal metaplasia of the surfaceepithelium and glandular metaplasia within a Brunn’s nest (cystitisglandularis).
50 µm
Fig 5: Bladder mucosa. Intestinal metaplasia of the surfaceepithelium, including goblet cells and a microvillous border.
100 µm
Fig 6: Bladder mucosa. TCC. Islands of mitotically active,neoplastic epithelial cells are infiltrating an inflamed laminapropria.
1985; Turner et al. 1995; Patterson-Kane et al. 2000) with onereport of a TCC of the renal pelvis (Servantie et al. 1986). This issimilar to man where >90% cases occur in the bladder (Tanakaand Sonpavde 2011).
No breed or sex predispositions are apparent from thereported cases. All affected horses were adults, with agesranging from 7 years to 15 years (mean 11.6 years). In dogs,studies have found that females are at higher risk than males(female:male ratio 1.7:1) with neutered individuals of bothsexes at higher risk (Mutsaers et al. 2003). This is in contrast toman, where the male to female ratio is 7:1 (Tanaka andSonpavde 2011). Risk factors identified in the dog includetopical flea and tick treatments, obesity and exposure to farminsecticides (Mutsaers et al. 2003). In man, smoking remains thehighest risk factor, with exposure to carcinogenic agents alsoidentified as a cause (Tanaka and Sonpavde 2011). No riskfactors have been identified to date in the horse.
Various clinical signs of TCC have been reported withhaematuria being the commonest presenting sign (reported in4/5 cases) followed by stranguria (2/5) and weight loss (2/5).Neurological deficits and fertility problems were observed in 2cases, as a result of metastatic spread (Traub et al. 1983; Turneret al. 1995). Other clinical signs included bladder dysfunction,recurrent urinary tract infections and colic. Haematuria andstranguria of acute onset were the first signs observed in thiscase. This is similar to the case reported in Patterson-Kane et al.(2000), where the horse presented with acute onset of severehaematuria. All other cases report clinical signs of morechronic duration (2 months–3.5 years).
Clinical signs of bladder neoplasia are similar to thatof cystic calculi. Rectal palpation and transrectalultrasonography can be used to differentiate between theseconditions. The use of cystoscopy allows direct visualisation ofthe bladder. It also enables biopsies of any mass to beperformed. In a study of 92 dogs with histologically diagnosedTCC, cystoscopic biopsy samples were of diagnostic quality in65% of male dogs and 96% of female dogs (Childress et al.2011).
The case described herein had no abnormalities onhaematological and serum biochemical evaluation. Otherpublished cases reported anaemia (2/4 cases), leucocytosiswith neutrophilia (3/4 cases) and hypokalaemia (1/4 cases).Urinanalysis was performed in 4/5 cases. All 4 cases reportedhaematuria and proteinuria with 2 cases also havingleucocyturia and visible bacteria which was similar to this case.Only one case had a positive bacterial culture (Turner et al.1995). It has been postulated that irritation to the bladder as aresult of chronic cystitis or pyelopnephritis may induceneoplasia (Fischer et al. 1985; Turner et al. 1995) although it isunlikely to be so in this case due to the absence of any clinicalsigns prior to presentation.
The cyclooxygenases (COX) catalyse the conversion ofarachidonic acid to prostaglandins. In most species, COX-1 is aconstitutive isoform expressed in many tissues and involvedprimarily in homeostatic functions, whereas COX-2 is principallyan inducible isoform, found at sites of inflammation (Smithet al. 2000). Epidemiological and experimental evidenceindicates that dysregulated inflammation is associated withcarcinogenesis in many tumours (Zhu et al. 2011). Inflammationcontributes to survival and proliferation of malignant cells,tumour angiogenesis, metastasis and reduced response tochemotherapy. In many species, including man and dogs,COX-2 is over-expressed in many different tumour types and
nonsteroidal anti-inflammatory drugs can be effectively usedas adjunctive therapies (Spugnini et al. 2005; Khan et al. 2011).Investigations on the expression of COX-2 in equine tumourshave yielded variable results and the significance of COX-2expression in equine neoplasia has still to be defined (Dore2011). There have, however, been a limited number of reports,both published and anecdotal, of successful treatment ofequine tumours (notably squamous cell carcinoma) by oraladministration of piroxicam, a nonselective cyclooxygenaseinhibitor (Moore et al. 2003; Elce et al. 2007; Iwabe et al. 2009;Serena et al. 2009). In the current case, the TCC was shownby immunohistochemistry to have a high level of COX-2expression and, for this reason, treatment with piroxicam wasinitiated. Whether or not this treatment aided in resolution orprevention of recurrence of the tumour is unclear. Inconclusion, TCC is an unusual tumour of the equine bladderthat can present with acute onset signs of haematuria andstranguria. The successful outcome of this case suggests thattreatment by surgical debulking and use of piroxicam can beeffective (assuming that no metastasis has occurred).However, further studies are required to elucidate theimportance of COX-2 expression and the potential role ofanti-inflammatory drugs in treatment.
Authors’ declaration of interestsNo conflicts of interest have been declared.
AcknowledgementsWe are grateful to Mr S. Brooks, MRCVS, for referring this horseto us and to colleagues at Bell Equine Veterinary Clinic and theDepartment of Veterinary Pathology, University of Bristol forassistance with the investigation and treatment of the case.
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