Urinary bladder tumours in the dog and cat

Spontaneous bladder tumours in the dog are predominantly malignant epithelial tumours, with the most frequent being transitional cell carcinomas (Fig. 1) which often involve the bladder trigone. Other reported histotypes are adenocarcinomas, squamous cell carcinomas, undifferentiated carcinomas and mesenchymal tumours, including rhabdomyosarcomas and fibrosarcomas._^1,2

 Bladder tumours have also been reported in the cat, although they seem to be less frequent in clinical practice. In this species, as in dogs, malignant tumours, especially of epithelial origin, are more common than mesenchymal tumours (which are usually benign). However, in cats, unlike in dogs, primary bladder lymphoma should be included among the possible neoplasms._³

Urethral tumours originate from the urethra; however, it is not always easy to determine whether involvement of the urethra is due to a primary tumour of the urethra or a bladder tumour with secondary involvement of the urethra. Also in the case of the urethra, epithelial tumours are more frequent, in particular transitional cell carcinomas._⁴

AETIOLOGY AND PATHOGENESIS

The aetiology of canine bladder tumours is not yet totally understood, although numerous studies suggest a multifactorial aetiology._⁵  The reported risk factors for bladder tumours are: exposure to herbicides and topical pesticides, obesity, the administration of cyclophosphamide, female sex and breed._{^{1,2, 6-8}}

With regards to exposure to herbicides and topical insecticides, Glickman et al_⁷  observed that the Scottish Terrier breed, which in notoriously genetically predisposed to the development of transitional cell carcinomas of the bladder, was at greater risk of developing bladder epithelial tumours when exposed to herbicides used in lawns and gardens, whereas, at least in their study, no statistically significant correlation was found with exposure to insecticides._⁷

As far as concerns a possible correlation with insecticides (e.g. flea-control products), a recent study did not find any association between transitional cell carcinoma of the bladder and the use of  “spot-on” flea-control products in dogs predisposed to the development of this tumour._⁸  Finally, one study found that the use of a diet rich in vegetables three times a week decreased the risk of developing bladder tumours in dogs of a predisposed breed._⁹

Transitional cell carcinomas of the bladder most commonly affect the trigone region,_^1,10,11 and may develop as both exophytic papillary lesions and as wall thickening which may cause partial or complete obstruction of the urinary tract.

EPIDEMIOLOGY

Urinary bladder tumours may potentially develop in any breed of dogs and cats. In the dog the breeds considered at risk, in decreasing order, are Scottish Terrier, Shetland Sheepdog, Beagle, Wirehaired Fox Terrier and West Highland White Terrier._¹ Female dogs are at a greater risk than male dogs, with a ratio which varies from 1.7:1_^1,2 to 1.95:1._¹¹

In cats, in the few case series published, bladder tumours seem to be more common among male animals._³

In both species the patients which develop bladder tumours are usually older adults, although mesenchymal tumours are more frequently encountered in young subjects._^12-15

Bladder tumours may spread to regional lymph nodes and to distant sites. At diagnosis, the metastases which are more commonly present are to the lymph nodes (10.5-16%)_^5,10 whereas in a post-mortem study of 102 cases, distant metastases were identified in 56% of patients._⁵

Most bladder tumours, especially transitional cell carcinomas, are classified, using ultrasonography and/or cystoscopy and following  the World Health Organization_¹  staging system,  as T2 tumours, with a small percentage classified as T3._^1-10

Table 1. TNM clinical staging of bladder tumours in the dog

SIGNS AND SYMPTOMS

Dogs with bladder tumours, and specifically with transitional cell carcinomas, may have haematuria, dysuria, pollakiuria, and, less frequently, lameness secondary to axial and appendicular skeletal involvement. Bladder tumours may also be an incidental finding during abdominal ultrasonography. During clinical examination, and specifically during rectal exploration, patients with bladder cancer may have detectable thickening of the trigone region and of the urethra (this is possible in the female) or enlargement of iliac lymph nodes. The identification of a bladder mass by simple abdominal manual palpation is extremely infrequent.

DIAGNOSTIC INVESTIGATIONS

Although bladder tumours may be suspected on the basis of clinical signs and symptoms, the definitive diagnosis must be made (with cytology and/or histology) in order to plan the diagnostic approach necessary to stage the tumour and to determine whether there is local spread (T), loco-regional lymph node involvement (N) or distant metastatic spread (M) of the tumour.

Abdominal ultrasonography often raises a strong suspicion of a bladder tumour (Fig. 2)._¹⁷ To reduce false positive results to a minimum the ultrasound examination should be done with the bladder distended. If the patient arrives with an empty bladder, it is suggested that the distension is induced by infusing 8 ml/kg of saline through a catheter (the catheterisation must be done with great caution, without forcing if masses are present at the trigone, in view of the risk of rupture and bleeding)._¹  Ultrasonography enables assessment of both the T and N components of the clinical staging system (Fig. 2). X-ray computed tomography may be used to complete the clinical staging. Another very good examination which can be used for staging patients and for a better classification/study of local disease before any surgery is “total body” computed tomography. Abdominal radiography with double contrast retrograde cystography, although rarely used and time-consuming, is an additional diagnostic tool which allows the diagnosis of local disease.

The above-mentioned examinations do not, however, provide a definitive diagnosis. Hence, in spite of the undoubted usefulness of these investigations for staging bladder tumours, before doing computed tomography of the patient, the cytological/histological diagnosis must be made.

The definitive diagnosis may be made from cytological examination of the urine or urethral mass. It is essential to remember that, in patients with a potential bladder tumour, centesis, to collect urine, or an echo-CT guided biopsy, for cytology, may potentially disseminate the tumour along the needle tract._^18-19  To reduce the risk of tumour dissemination urine samples should be collected with a urethral catheter, or, as an alternative, a lesion may be biopsied with a catheter or with a cystoscopy-guided “pinch biopsy”, done under anaesthesia. The decision on whether to take samples by catheterisation must be pondered carefully, in view of the risk of causing iatrogenic bladder trauma._¹

Biopsies by means of coeliotomy or cystotomy are possible, but these strategies must be carefully assessed together with the owner, as these are real and proper surgical interventions. These approaches should not be excluded in dogs which present with complete obstruction of the urinary tract. In such cases coeliotomy and cystotomy could be both diagnostic and palliative therapeutic interventions, as they enable insertion of a prepubic catheter_²⁰ which may temporarily resolve the obstructive emergency and thereby allow diagnosis of the case, staging of the disease, planning of the therapy (surgery, chemotherapy or radiotherapy) and definition of the prognosis. Urethral stents may be an alternative to these procedures, in the case of malignant obstructions of the lower urinary tract._^21,22

 DIFFERENTIAL DIAGNOSES

Possible differential diagnoses are:

• Granulomatous urethritis/cystitis 
• Bladder stones
• Polypoid cystitis

TREATMENT

Therapeutic options for the treatment of bladder tumours are surgery, radiotherapy and chemotherapy.

Surgery
Surgical removal of bladder tumours has proven of limited use in terms of achieving an acceptable oncological result in cases of transitional cell carcinomas located at the trigone. Indeed, apart from the objective difficulty of achieving clean surgical margins, these bladder tumours often relapse in the same organ, as some dogs have multiple transitional cell carcinomas; this is similar to what happens in humans, in whom the entire organ is potentially exposed to carcinogenesis._²³ The surgical approach in this anatomical site may, therefore, require complete ablation of the trigone and of the bladder itself, followed by transposition of the ureters to the descending colon or, in the female, to the uterus/bladder. Such interventions may be followed by a complicated post-operative period, with the development of ureteritis, ascending nephritis as well as urinary incontinence. A new technique has recently been described, in a limited number of patients, which allows the complete removal of the bladder trigone with re-implantation of the ureters into the bladder itself. _²⁴

Although the therapeutic/surgical goal of urethral stents is not directly related to the oncological outcome, such stents are a valid alternative to the placement of cystostomic catheters in the emergency management of dogs with obstruction of the urinary tract. Urethral stents improve the quality of life of patients waiting for and during staging procedures and during cytoreductive treatments such as chemotherapy and radiotherapy._²¹ In the study by Weiss the limited number of cases and the emergency conditions in which stents were used did not allow sufficient data to be collected in order express an opinion on the oncological outcome._²¹

Although the use of laser technology to remove bladder tumours does not confer a survival advantage, it has been shown to reduce post-operative complications. Studies on this specific aspect of surgery of bladder tumours are, however, scarce._²⁵

Transitional cell carcinomas at the apex of the bladder are less frequent, but are amenable to relatively simple surgery, such as partial cystectomy, which might, however, not prevent subsequent relapse in the organ as the patient may be predisposed to developing bladder tumours.

Radiotherapy
Radiotherapy was used in the past for the treatment of bladder tumours, especially as an intra-operative procedure; however, many complications were reported, such as urinary incontinence, cystitis, pollakiuria and strangury, with a negative impact on the quality of life of the patient._²⁶ More recently, a study suggested the combined use of mitoxantrone, piroxicam  and radiotherapy, showing that a modified way of administering the radiotherapy reduced the incidence of complications. The overall survival was not, however, increased compared to that achieved with other protocols using only chemotherapy._²⁷

Chemotherapy
Various protocols have been suggested for the treatment of urinary bladder tumours and many of the studies have focused specifically on the treatment of transitional cell carcinomas of the bladder. Cyclo-oxygenase-1 and -2 inhibitors are often combined with chemotherapeutic drugs such as cisplatin, carboplatin and mitoxantrone. The cyclo-oxygenase inhibitor most frequently mentioned in the literature is piroxicam.

Despite the various protocols available and the convincing oncological results of cisplatin, with or without piroxicam, it has now been ascertained that the renal toxicity of this drug is unacceptable._²⁸

The following table summarises the results obtained in clinical trials on the use of chemotherapy in the treatment of transitional cell carcinomas of the bladder.

Table 2. Results obtained with chemotherapy in the treatment of transitional cell carcinomas of the bladder. *CR:  complete remission, defined by the macroscopic disappearance of the tumour; PR: partial remission, defined by a 50% or greater reduction in the size of a tumour which is still visible, in the absence of new lesions.

The above table is only a summary of the data available. Protocols with carboplatin, mitoxantrone, as well as recent protocols with gemcitabine, certainly seem to show positive results with limited toxicity, although none prevails over the others.

PROGNOSIS

The prognosis of patients with bladder tumours, especially transitional cell carcinomas, seems poor, as less than 20% of treated patients are alive at 1 year, regardless of the surgery, chemotherapy and radiotherapy employed.

References

1. Knapp DW. Tumors of the urinary system. In: Withrow SJ, VailDM, eds. Withrow & MacEwen’s small animal clinical oncology.4th ed. Philadelphia: WB Saunders Co, 649–658, 2007.
2. Mutsaers AJ, Widmer WR, Knapp DW. Canine transitional cell carcinoma. J Vet Intern Med, 17:136–144, 2003.
3. Wilson HM, Chun R, Larson VS, et al. Clinical signs, treatments, and outcome in cats with transitional cell carcinoma of the urinary bladder: 20 cases (1990-2004). J Am Vet Med Assoc, 231(1):101-6, 2007.
4. Davies JV,  Read HM. Urethral tumours in dogs. J Small Anim Pract, 31:131-136, 1990.
5. 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. Urol Oncol, 5(2):47-59, 2000.
6. 6.Glickman NW,  Schofer FS,  McKee IJ. Epidemiologic study of insetticide exsposure, obesity, and risk of bladder cancer in household  dogs.  J toxicology Environ  Health, 28:407-414, 1989.
7. 7.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, 224:1290-7, 2004.
8. 8.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 225:389-94, 2004.
9. Raghavan M, Knapp DW, Bonney PL, et al. Evaluation of the effect of dietary vegetable consumption on reducing risk of transitional cell carcinoma of the urinary bladder in Scottish Terriers.J Am Vet Med Assoc, 227:94-100, 2005.
10. Marconato L, Zini E, Lindner D, et al. Toxic effects and antitumor response of gemcitabine in combination with piroxicam treatment in dogs with transitional cell carcinoma of the urinary bladder.J Am Vet Med Assoc, 238:1004-10, 2011.
11. 11.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,  6:145-53, 1992.
12. 12.Bae IH, Kim Y, Pakhrin B, et al. Genitourinary rhabdomyosarcoma with systemic metastasis in a young dog.Vet Pathol, 44:518-20, 2007.
13. 13.Olausson A, Stieger SM, Loefgren S, et al. A urinary bladder fibrosarcoma in a young dog. Vet Radiol Ultrasound, 46:135-8, 2005.
14. Kuwamura M, Yoshida H, Yamate J, et al. Urinary bladder rhabdomyosarcoma (sarcoma botryoides) in a young Newfoundland dog. J Vet Med Sci, 60:619-21, 1998.
15. Kim DY, Hodgin EC, Cho DY, et al. Juvenile rhabdomyosarcomas in two dogs.Vet Pathol, 33:447-50, 1996
16. Owen LN: TNM classification of tmours in domestic animals. Geneva, 1980, World Health Organization .
17. 17.Hume C, Seiler G, Porat-Mosenco Y, et al. Cystosonographic measurements of canine bladder tumours.Vet Comp Oncol,  8:122-6, 2010.
18. 18.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, 43:50-3, 2002
19. Vignoli M, Rossi F, Chierici C, et al. Needle tract implantation after fine needle aspiration biopsy (FNAB) of transitional cell carcinoma of the urinary bladder and adenocarcinoma of the lung.Schweiz Arch Tierheilkd, 149(7):314-8, 2007.
20. Smith JD, Stone EA, Glison SD.  Placement of a permanent cystostomy catheter to relieve urine outflow obstruction in dogs with transitional  cell carcinoma. J Am Vet Med Assoc, 206:496-499, 1995.
21. 21.Weisse C, Berent A, Todd K, et al. Evaluation of palliative stenting for management of malignant urethral obstructions in dogs.J Am Vet Med Assoc, 229:226-34, 2006.
22. 22.Christensen NI, Culvenor J, Langova V. Fluoroscopic stent placement for the relief of malignant urethral obstruction in a cat.Aust Vet J, 88:478-82, 2010.
23. Fair  WR, Fuks ZY, Scher HI. Cancer of bladder. In DeVita VT, Hellman S, Rosenberg SA editors: Principles and practice of oncology, ed 4, Philadelphia, 1993, JB Lippincott.
24. Saulnier-Troff FG, Busoni V, Hamaide A.A technique for resection of invasive tumors involving the trigone area of the bladder in dogs: preliminary results in two dogs. Vet Surg, 37:427-37 2008.
25. Upton ML, Tangner CH, Payton ME. Evaluation of carbon dioxide laser ablation combined with mitoxantrone and piroxicam treatment in dogs with transitional cell carcinoma. J Am Vet Med Assoc, 228:549-52, 2006.
26. Walker M, Breider M. Intraoperative radiation therapy canine bladder cancer. Vet Radiol, 28: 200-204, 1987.
27. Poirer VJ, Forrest LJ, Adam WM et al. Piroxicam, mitoxantrone, and coarse fraction radiation therapy for the treatment of transitional cell carcinoma of the bladder in 10 dogs : a pilot study. J Am Anim Hosp Assoc, 40: 131-136, 2004.
28. Greene SN, Lucroy MD, Greenberg CB, et al. Evaluation of cisplatin administered with piroxicam in dogs with transitional cell carcinoma of the urinary bladder. J Am Vet Med Assoc, 231:1056-60, 2007.
29. 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, 209:1588-91, 1996.
30. 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,  4:148-52, 1990.
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, 8:273-8, 1994.
32. Chun, R, Knapp DW, Winder WR et al. Phase II clinical trial of carboplatin in canine transitional cell carcinoma of the urinary bladder. J Vet Intern Med 11:279-283, 1997
33. 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. 2:183-8, 2003.
34. 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, 3:73-80, 2005.
35. 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, 9:906-11, 2003
36. Abbo AH, Jones DR, Masters AR, et al. Phase I clinical trial and pharmacokinetics of intravesical mitomycin C in dogs with localized transitional cell carcinoma of the urinary bladder J Vet Intern Med, 24:1124-30, 2010.