Tumors of the Urinary System

29 

Tumors of the Urinary System Deborah W. Knapp and Sarah K. McMillan

Canine Urinary Bladder Tumors Urinary bladder cancer accounts for approximately 2% of all reported malignancies in the dog.1-4 With more than 70 million dogs in the United States, even uncommon forms of cancer affect thousands of dogs each year.2,3 The hospital prevalence or proportionate morbidity of bladder cancer at university-based veterinary hospitals is increasing.2 Invasive transitional cell carcinoma (TCC) is the most common form of canine urinary bladder cancer.1-4 Most TCCs are intermediate- to high-grade papillary infiltrative tumors.2-4 Other types of bladder tumors reported less frequently include squamous cell carcinoma, adenocarcinoma, undifferentiated carcinoma, rhabdomyosarcoma, lymphoma, hemangiosarcoma, fibroma, and other mesenchymal tumors.4-10 TCC is most often located in the trigone region of the bladder. Papillary lesions and a thickened bladder wall (Figure 29-1) are common features and can lead to partial or complete urinary tract obstruction. In a series of 102 dogs with TCC of the bladder, the cancer also involved the urethra in 56% of dogs and involved the prostate in 29% of male dogs.2 Nodal and distant metastases were present in 16% and 14% of dogs, respectively, at diagnosis.2 At the time of death, distant metastases were detected in 50% of the dogs.2 Following World Health Organization (WHO) criteria for staging canine bladder tumors11 (Box 29-1), 78% of dogs had T2 tumors and 20% had T3 tumors.2

Etiology and Prevention

The etiology of canine bladder cancer is multifactorial. Risk factors include exposure to older-generation flea control products and lawn chemicals, obesity, possibly cyclophosphamide exposure, female sex, and a very strong breed-associated risk (Table 29-1).1,2,12-15 The female : male ratio of dogs with TCC has been reported to range from 1.71 : 1 to 1.95 : 1.1-3 TCC risk is higher in neutered dogs than in intact dogs of both sexes, although the reason for this has not been determined.2,13 Two case control studies have implicated chemical exposure in TCC risk in dogs. In a case control study of dogs of several breeds, an association between TCC and exposure to topical flea and tick dips was noted.12 In the highest risk group (overweight female dogs), the risk of TCC was 28 times that of normal-weight male dogs not exposed to the insecticides.12 The authors speculated that the “inert” ingredients (solvents and petroleum distillates), which accounted for more than 95% of the product, were the probable carcinogens. Newer, spot-on type flea control products appear safer. In a case control study in Scottish terriers, spot-on products containing fipronil were not associated with increased risk of TCC.14 In a case control study in Scottish terriers (STs), exposure to lawn herbicides and pesticides was compared between STs with TCC (n = 83) and a control group of STs (n = 83, ≥6 years of age,

572

no history of urinary tract disease in the previous 2 years).15 TCC risk was significantly higher in STs that had been exposed to lawn herbicides alone (odds ratio [OR], 3.62; 95% confidence interval [CI] 1.17 to 11.19; p <0.03) or herbicides and insecticides (OR, 7.19; 95% CI 2.15 to 24.07; p <0.001) than in dogs not exposed.15 A positive finding in the STs study was that dogs that ate vegetables at least three times a week, along with their normal diet, had a reduced risk of TCC (OR, 0.30; 95% CI 0.01 to 0.97; p <0.001).16 The specific type of vegetable with the most benefit could not be determined, but carrots, given as treats, were the most frequently fed vegetable in the study. Although prospective prevention studies have not yet been performed, it would appear appropriate to limit exposure to lawn chemicals and older types of flea control products and to feed vegetables at least three times per week, especially in dogs in breeds with high risk for TCC. The owners of dogs in high-risk breeds should be informed of the TCC risk and encouraged to take note of urinary tract signs should they occur and to pursue veterinary care in a timely fashion. Prospective studies to determine the value of TCC screening and early detection have not yet been reported.

Diagnosis and Differential Diagnoses

Many conditions can mimic TCC in regards to clinical signs, abnormal epithelial cells in urine, and mass lesions within the urinary tract (Figures 29-2 and 29-3; Table 29-2). Differential diagnoses include other neoplasia, chronic cystitis, polypoid cystitis, fibroepithelial polyps, granulomatous cystitis/urethritis, gossypiboma, calculi, and inflammatory pseudotumor.4-10,17-21 It is important to distinguish non-TCC conditions from TCC because the treatment and prognosis differ considerably and depend on the condition present. A diagnosis of TCC requires histopathologic confirmation. Although neoplastic cells may be present in the urine of 30% of dogs with TCC,4 neoplastic cells often are indistinguishable from reactive epithelial cells associated with inflammation. Urine antigen tests for TCC have been found to be sensitive,22 but a high number of false-positive results limits the value of these tests. A bladder or urethral mass may raise suspicion for TCC, but as discussed previously, other conditions can cause bladder and urethral masses (see Figures 29-2 and 29-3 and Table 29-2). Therefore histopathologic examination of the abnormal tissues is essential to determine whether TCC is present. In addition, different pathologic types of TCC can be identified with histopathology.4,21 Methods for obtaining tissue for histopathologic diagnosis include cystotomy, cystoscopy (see Figure 29-2), and traumatic catheterization.2,23-25 Cystoscopy provides the opportunity to visually inspect the urethra and bladder and to obtain biopsies in a noninvasive method. With the small size of cystoscopic biopsies, the operator must be diligent to collect sufficient tissue for

Chapter 29  Tumors of the Urinary System  573 • Table 29-1 Breed and Risk of Transitional Cell Carcinoma (TCC) in Pet Dogs* Breed

• Figure 29-1 Papillary invasive transitional cell carcinoma observed in the urinary bladder of a dog during postmortem examination. (Courtesy T. Lin, Purdue University.)

Box 29-1

TNM Clinical Staging System for Canine Bladder Cancer

T—Primary Tumor Tis T0 T1 T2 T3

Carcinoma in situ No evidence of a primary tumor Superficial papillary tumor Tumor invading the bladder wall, with induration Tumor invading neighboring organs (prostate, uterus, vagina, and pelvic canal)

N—Regional Lymph Node (Internal and External Iliac Lymph Node) N0 N1 N2

No regional lymph node involvement Regional lymph node involved Regional lymph node and juxtaregional lymph node involved

M—Distant Metastases M0 M1

No evidence of metastasis Distant metastasis present

Modified from Owen LN: TNM classification of tumours in domestic animals, Geneva, 1980, World Health Organization.

diagnosis. Placing tissue samples in a histology cassette prior to processing helps prevent loss of small samples (see Figure 29-2, F). In a recent report of 92 dogs, diagnostic samples were obtained by cystoscopy in 96% of female dogs and 65% of male dogs that ultimately had hisotopathologically diagnosed TCC.25 The more recent use of a wire basket designed to capture stones during cystoscopy (see Figure 29-2, D and E) allows collection of larger samples and is expected to increase the yield of diagnostic biopsy samples. Traumatic catheterization to collect tissues for diagnosis can also be

Mixed breed All purebreds Scottish terrier Shetland sheepdog Beagle Wire-haired fox terrier West Highland white terrier Miniature schnauzer Miniature poodle Doberman pinscher Labrador retriever Golden retriever German shepherd

Odds Ratio

95% Confidence Interval

1.0† 0.74 18.09 4.46 4.15 3.20 3.02 0.92 0.86 0.51 0.46 0.46 0.40

— 0.62-0.88 7.30-44.86 2.48-8.03 2.14-8.05 1.19-8.63 1.43-6.40 0.54-1.57 0.55-1.35 0.30-0.87 0.30-0.69 0.30-0.69 0.26-0.63

Modified from previous report by 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 5:47–59, 2000. *This table represents a summary of data from 1290 dogs with TCC and 1290 institution and age-matched control dogs without TCC in the Veterinary Medical Data Base. † Reference category.

performed, although samples collected by this method are usually small and the diagnostic quality varies considerably from case to case. Percutaneous biopsy methods can lead to tumor seeding and are best avoided.26,27 In poorly differentiated carcinomas, immunohistochemistry for uroplakin III (UPIII) can be helpful in distinguishing TCC from other carcinomas. UPIII, a transmembrane protein expressed in superficial transitional epithelial cells in the urinary tract, is expressed in more than 90% of canine TCC and has been considered a specific marker for TCC.28 Recently, UPIII expression has also been reported in canine prostate cancer,29 although it is not known if the immunoreactive cells originated from the transitional epithelium of the prostatic ducts or elsewhere in the gland.

Presentation and Clinical Staging

Common clinical signs in dogs with TCC include hematuria, dysuria, pollakiuria, and, less commonly, lameness caused by bone metastasis or hypertrophic osteopathy.1 Urinary tract signs may be present for weeks to months and may resolve temporarily with antibiotic therapy. In dogs with TCC, a physical examination, which includes a rectal examination, may reveal thickening of the urethra and trigone region of the bladder, enlargement of iliac lymph nodes, and sometimes a mass in the bladder or a distended bladder. However, normal findings on a physical examination do not rule out TCC. In dogs with confirmed or suspected TCC, evaluation should include an assessment of overall health (complete blood count [CBC], serum biochemistry profile, urinalysis, ± urine culture) and staging of the cancer (thoracic radiography, abdominal ultrasonography, and urinary tract imaging). To avoid the risk of seeding TCC through cystocentesis, urine may be collected by free catch or

574  Part IV Specific Malignancies in the Small Animal Patient

A

B

C

D

E

F

G

H

I

• Figure 29-2 A to E, Images from cystoscopy of dogs with transitional cell carcinoma (TCC) and biopsy material obtained (F), and images of dogs with polypoid cystitis (G to I). TCC can appear as a ruffled frond-like mass or less commonly as polyp-like lesions. The images obtained with rigid cystoscopes typically used in female dogs (A and C to E) are usually better than those obtained with smaller diameter flexible scopes used in male dogs (B, image from a male Scottish terrier), although both types of cystoscopes allow adequate visualization for biopsy. The use of a cystoscopic wire stone basket (D and E) allows collection of larger biopsies. Regardless of the biopsy instrument used, however, cystoscopic biopsies are relatively small, and placing the samples in a tissue cassette (F) may facilitate processing. Polypoid cystitis (G to I) appears very similar to TCC, but it is treated differently and has a better prognosis than TCC. Dog with polypoid cystitis before (H) and after (I) a month of clavamox treatment alone with no other therapy. The polpys had regressed by >80% (I) at the time of rescoping. Cases such as this one emphasize the importance of histopathology in the diagnosis of urinary tract masses, especially when selecting therapy, and even more so when dogs are participating in clinical trials. (Courtesy L.G. Adams, Purdue University.)

catheterization. If a catheter is to be passed, care must be taken to avoid penetrating the diseased bladder or urethral wall. Common sites of metastases detected with thoracic radiography and abdominal ultrasonography include lymph nodes, liver, and lungs, although metastases can occur in other areas as well.1-3 TCC infrequently

metastasizes to bone. Side-by-side comparison of radiographs and a nuclear bone scan may help detect possible bone metastases in dogs with unexplained lameness or bone pain. Urinary tract imaging is used to assess the TCC location for potential surgical intervention and to map and measure TCC

Chapter 29  Tumors of the Urinary System  575

A

B

C

D

• Figure 29-3 Cystosonography images from dogs with bladder masses. Note images made in the sagittal (A) and transverse (B) planes (5 mL/kg fluid distension of the bladder) of an 11-year-old neutered male Shih Tzu with transitional cell carcinoma (TCC). To measure bladder masses over multiple time points, it is important to follow a consistent protocol in regards to level of bladder distension, and patient and probe positioning; and to have the same operator perform the ultrasonography on each visit. Polypoid cystitis (C and D), which can appear very similar to TCC, can occur in any part of the bladder, including the mid/apex (C) and trigone (D). The dog imaged in D was a 13-year-old spayed female Bichon Frise with history of previous urinary tract infection, current hematuria, stranguria, atypical epithelial cells in urine, and masses in the mid/apex and trigone areas of the bladder. Surgical biopsies of the masses confirmed polyps. (Courtesy J.F. Naughton, Purdue University.)

masses in order to subsequently determine response to medical therapy. Mapping TCC in the bladder, proximal urethra, and prostate can be accomplished by cystosonography (see Figure 29-3), cystography, or computed tomography (CT).30,31 Regardless of the imaging technique used, to accurately track response to therapy, it is important to follow a consistent protocol from visit to visit for bladder distension and patient positioning. In addition, when using cystosonography to monitor therapy response, it is critical to have the same operator perform the examinations over multiple visits.

Treatment

Surgery and Nonsurgical Procedures

In dogs with TCC, surgery may be indicated for one or more of the following reasons: (1) to obtain tissue for a diagnosis, (2) to attempt to remove the TCC within the bladder if lesions are away from the trigone, and (3) to maintain or restore urine flow. The potential value of cytoreductive surgery to enhance the activity of adjuvant therapy requires further study. If surgery is performed, it is crucial to take measures to avoid seeding the cancer. Complete surgical excision of TCC is not usually possible because of the typical trigonal location, urethral involvement, and metastases in some cases. Although techniques for trigone

resection32 or cystectomy33,34 and the use of grafting materials to replace bladder tissues35,36 have been reported in the dog, these approaches are associated with substantial morbidity and expense and in most cases are not feasible. In addition, many dogs develop multifocal TCC in the bladder, consistent with the “field effect” proposed in humans in which the entire bladder lining is thought to undergo malignant change in response to carcinogens in the urine. In a series of 67 dogs with TCC that underwent surgery for biopsy or for therapeutic intent, complete surgical excision of the tumor with tumor-free margins was possible in only two dogs.2 One of the two dogs had a relapse in the bladder 8 months later, and the second dog developed metastatic disease. Although surgery is rarely curative in dogs with TCC, surgery can be important in restoring or maintaining urine flow. Ureteral stents, when indicated, have traditionally been placed surgically, although less invasive techniques to place stents have recently been described.37 Previously described ureterocolonic anastomosis is not recommended due to the high complication rate and limited survival.38 Prepubic cystostomy catheters that bypass urethral obstruction can be very effective.39,40 More recently, the placement of urethral stents has gained favor over cystotomy tubes in some cases because external tubes are avoided and the pet owner does not have to drain the bladder.41 The survival following stent placement can

576  Part IV Specific Malignancies in the Small Animal Patient • Table 29-2 Characteristics of 21 Dogs Presented to the Purdue University Veterinary Teaching Hospital (PUVTH) in Recent Years With Bladder/Urethral Masses Caused by Conditions Other Than Transitional Cell Carcinoma (TCC)* Histopathologic Diagnosis

Dogs (no.)

Age (years)

Sex

Breed

Location of Bladder Lesions

4 FS, 3 MN

M MN FS FS FS

6 pure bred† and 1 mixed breed 6 pure bred‡ and 1 mixed breed 1 beagle, 1 Scottish terrier German shepherd Scottish terrier mix Greyhound Miniature dachshund Golden retriever

Multiple masses; involved trigone area in 4 cases Lesions involved the trigone in 6 cases Thick, irregular wall, involved trigone in both dogs Entire bladder wall Outside bladder¶ Trigone Trigone and urethra Midbody

Polypoid cystitis

7

Cystitis/urethritis

7

Hyperplasia in absence of inflammation§ Inflammatory pseudotumor|| Hydronephrosis¶ Leiomyosarcoma Plasma cell tumor Fibroblastic proliferation and stromal polyp

2

Median 10, range 5-13 Median 8, range 4-12 9, 9

1 1 1 1 1

12 8 12 11 8

7 FS 1 FS, 1 MN

FS, Female spayed; MN, male neutered; M, male. *Excludes dogs with prostatic carcinoma or other prostatic disease and dogs with cystic calculi. † One each of the following: Australian shepherd, Jack Russell terrier, Bichon Frise, Swiss mountain dog, golden retriever, Rhodesian ridgeback. ‡ One each of the following: German shepherd, Great Dane, Cocker spaniel, English Springer spaniel, West Highland white terrier, Chesapeake Bay retriever. § One dog had surgical biopsies. The other dog had cystoscopic biopsies and no evidence of progression to TCC >2 years later. || The dog was presented for urinary obstruction and bladder mass. Prior to presentation at the PUVTH, surgery had been performed to remove a testicle from the abdomen. The testicle and spermatic cord were noted to be wrapped around the urethra. The mesenchymal changes were thought to be due to the bladder response to chronic urethral obstruction. ¶ The dog was referred to the PUVTH for inappropriate urination and abdominal mass. Based on signalment and history, TCC was included on the differential list. Ultrasonography and computed tomography (CT) demonstrated a large cystic mass associated with the right kidney. A 15 × 10 × 10 cm mass containing 500 mL of fluid was removed surgically. Histopathology of the mass revealed renal atrophy, fibrosis, and moderate hydronephrosis, most likely due to a urinary obstruction event. No cause for urinary obstruction was found, and the dog was normal at last follow-up 7 months post op.

vary considerably from dog to dog. In preliminary findings from Purdue University, survival following stent placement in dogs ranged from a few days to a year.42 Urethral stents can be placed nonsurgically with fluoroscopic guidance. Although there has been interest in the potential use of laser ablation of tumor tissue to relieve urethral obstruction, in published work to date this has not been successful due to advanced local disease, complications of the procedure, and local disease recurrence.43 One of the challenges in transurethral resection is the difficulty in judging the deeper tumor margin and the risk of cutting too deep and perforating the urinary tract.

Radiation Therapy

Information on the use of radiation therapy (RT) in TCC and other bladder tumors is limited.44,45 In one report, one of seven dogs treated with intraoperative radiation was alive at 1 year.45 In another report of 13 dogs, the 1- and 2-year survival rates following intraoperative RT were 69% and 23%, respectively, but complications of therapy (i.e., urinary incontinence and cystitis with accompanying pollakiuria and stranguria) detracted from the dogs’ quality of life.44 Other studies have confirmed complications associated with pelvic irradiation.46 A laparoscopically implanted tissue expander to reduce exposure to surrounding organs during RT of the bladder has been described, but this approach requires more study before routine use.47 In a report of 10 dogs, weekly coarse fraction externalbeam RT combined with mitoxantrone and piroxicam was tolerated, but results were no better than those with medical therapy alone.48 Studies of intensity-modulated RT (IMRT) for TCC are ongoing.

Medical Therapy

Systemic Medical Therapy  Systemic medical therapy is the

mainstay of TCC treatment in dogs and usually consists of chemotherapy, cyclooxygenase (COX) inhibitors (nonselective COX inhibitors and COX-2 inhibitors), and combinations of these (Table 29-3).* Although medical therapy is not usually curative, several different drugs can lead to remission or stable disease of TCC, and most therapies are well tolerated. Resistance to one drug does not necessarily imply resistance to other drugs. Some of the best results are seen in dogs that sequentially receive multiple different treatment protocols over the course of their disease. The approach used at the Purdue University Veterinary Teaching Hospital (PUVTH) is to obtain baseline measurements of the TCC masses, to initiate a starting treatment, to monitor the response to that treatment at 4- to 8-week intervals, and to continue that treatment as long as the TCC is controlled, side effects are acceptable, and quality of life is good. If cancer progression or unacceptable toxicity occurs, then a different treatment is instituted. Subsequent treatment changes are based on tumor response and treatment tolerability. By following this approach, TCC growth can be controlled in approximately 75% of dogs, the dogs’ quality of life is usually very good, and median survival times (MSTs) can extend well beyond a year. Although it could be tempting to simultaneously combine multiple chemotherapy agents in dogs with TCC, the benefit of this has not been determined and the potential development of resistance to multiple drugs at the same time could limit the options for subsequent therapy. *References 1-3, 30, 49-51, 53-56, 58-60.

Chapter 29  Tumors of the Urinary System  577 • Table 29-3 Study Results Reported for the Medical Therapy of Transitional Cell Carcinoma (TCC) in Dogs*

Drug

Dogs (no.)†

N1 or N2/ M1/Any Metastasis (% of Total Dogs)

CR (%)

PR (%)

SD (%)

PD (%)

PFI (days)

Median Survival From Start of Drug (days)

34 26/24 55/48 28/28 18/16 15/12 14 14/12

20/15/23 4/11/15 NA/NA/11 11/21/28 NA/28/33 27/33/40 7/7/7 14/14/28

6 0 2 0 0 0 0 0

12 17 33 36 19 25 7 50

53 71 46 50 25 50 36 17

29 12 19 14 56 25 57 33

NA 133 194 122 75 NA 78 NA

181 323 291 147|| 130 105 307 329

49 50 51 52 53 54 55 55

14 /12 31/29 13/12 38/37

21/14/28 13/13/19 0/0/0 11/3/11

0 0 0 5

0 38 42 22

8 45 58 51

92 17 0 22

41 NA 120 NA

132 161 223 230

30 56 57 58

8 14

12/12/12 28/14/43

0 14

0 57

50 28

50 0

84 124

300¶ 246

59 59

Reference

Single-Arm Trials

Piroxicam‡ Deracoxib‡ Mitoxantrone/piroxicam§ Vinblastine‡|| Cisplatin (60 mg/m2)‡ Cisplatin (50 mg/m2)‡ Cisplatin (40-50 mg/m2)‡ Cisplatin (60 mg/m2)/ piroxicam‡ Carboplatin‡ Carboplatin/piroxicam‡ Mitomycin C—intravesical‡ Gemcitabine/piroxicam§ Randomized Trials

Cisplatin (60 mg/m2)‡ Cisplatin (60 mg/m2)/ piroxicam‡**

CR, Complete remission; PR, partial remission; SD, stable disease; PD, progressive disease; PFI, progression-free interval; NA, information not available. *More advanced TNM stage is associated with a poorer prognosis; the percentages of dogs with metastasis for each study are included. † Total/evaluable for tumor response. ‡ Diagnosis based on histopathology. § Study included dogs with cytologic evidence of TCC and dogs with biopsy-proved TCC. || The majority of dogs had failed prior therapy before receiving vinblastine. The dosage of vinblastine used in this trial was 3 mg/m2 every 2 weeks. In most dogs in the trial, however, subsequent dose reduction was necessary because of myelosuppression. Currently, at our institution, the starting dosage of vinblastine for dogs with TCC is 2.5 mg/m2 every 2 weeks for medium to large dogs and 2.25 mg/m2 every 2 weeks for small dogs. ¶ Dogs that initially received cisplatin alone and had tumor progression were then treated with piroxicam alone; two dogs had PR, and five dogs had SD with piroxicam treatment. This may have contributed to the favorable survival in that treatment arm. **Despite favorable tumor response, the combination of cisplatin and piroxicam is not recommended for routine use due to frequent renal toxicity.

Two treatment approaches that have been used most commonly in dogs with TCC are (1) a single-agent COX inhibitor and (2) mitoxantrone combined with a COX inhibitor. As a single agent, the nonselective COX inhibitor, piroxicam, is a useful palliative treatment for dogs with TCC.1-3,49 The quality of life in dogs that receive piroxicam has been excellent. Responses in 62 dogs with TCC that received piroxicam as a single agent included two complete remissions (CR), nine partial remissions (PR, ≥50% decrease in tumor volume), 35 stable diseases (SD, <50% change in tumor volume), and 16 progressive diseases (PD, ≥50% increase in tumor volume or new tumor masses). The two dogs that had CR died of non–tumor-related causes more than 2 years after beginning piroxicam therapy and were free of tumor at necropsy. The survival time (median 195 days) compared favorably to that of 55 dogs in the Purdue Comparative Oncology Program Tumor Registry that were treated with cytoreductive surgery alone (median survival 109 days).2 Piroxicam is administered at a dosage of 0.3 mg/kg PO once daily in dogs. Although most dogs tolerate the drug well, care must be taken to watch for gastrointestinal (GI) toxicity, particularly ulceration. If vomiting, melena, and anorexia occur, the drug must be withdrawn and supportive care provided as needed until the

toxicity resolves. In these cases, it may be safest to switch to a COX-2 inhibitor if further COX inhibitor treatment is indicated. A COX-2 inhibitor, deracoxib (Dermaxx, Novartis), has been evaluated as a single agent at a dosage of 3 mg/kg PO daily in 26 dogs with TCC.50 Tumor responses included four (17%) PR, 17 (71%) SD, and three (12%) PD. The median survival following deracoxib and subsequent therapies was 323 days. Mild GI toxicity occurred in 20% of dogs, and 4% of dogs had renal or hepatic side effects. The 17% remission rate with deracoxib appears comparable to the remission rate with piroxicam; however, occasional CRs occur in dogs receiving piroxicam, whereas CR was not noted in dogs treated with deracoxib. In a pilot study at the PUVTH, adjuvant deracoxib was given to nine dogs (four spayed female, three neutered male, and two intact male dogs) following surgical removal of TCC.61 Three dogs had tumor-free margins, and six dogs had microscopic TCC present in surgical margins. Deracoxib (3 mg/kg PO daily) was instituted postoperatively. Of three dogs with tumor-free margins, recurrence (consistent with the field effect) was noted in two dogs at 210 and 332 days, respectively. The third dog died with no relapse detected at 1437 days. Of six dogs with microscopic residual TCC after

578  Part IV Specific Malignancies in the Small Animal Patient surgery, recurrence was noted in two dogs at 140 and 231 days, respectively. One of the six dogs is alive, tumor free, and still receiving deracoxib at 2057 days. Three dogs with microscopic residual TCC have died with no relapse detected at 345, 749, and 963 days. The median survival of the nine dogs was 749 days (range 231 to 2581 days). Without a randomized trial comparing deracoxib to placebo, it is not possible to know the extent to which deracoxib may have prolonged the disease-free interval in these dogs. The findings, however, of no relapse in four dogs with residual microscopic TCC following surgery at 345, 749, 963, and 2057 days are encouraging. In unpublished work, another COX-2 inhibitor, firocoxib (Previcox, Merial) has also had antitumor activity against canine TCC.62. It is not yet known if nonselective COX inhibitors and COX-2 inhibitors are equally effective in treating TCC. COX-2 inhibitors, however, offer an advantage of less GI toxicity. The most commonly used chemotherapy protocol in dogs with TCC is mitoxantrone combined with piroxicam.51 In a study of 55 dogs, 35% of dogs had remission with minimal toxicity, and the median survival was 291 days (n = 55).51 Although a higher remission rate (50% to 70%) has been noted with cisplatin combined with piroxicam, this protocol is limited by frequent renal damage.55,59,60 Lowering the cisplatin dose did not reduce the renal toxicity of this combination.55 Carboplatin, a platinum drug with less renal toxicity, was combined with piroxicam. Remission occurred in 38% of dogs with TCC, but the median remission duration and survival were relatively short.56 In a recent study, gemcitabine (800 mg/m2) and piroxicam were given to dogs with cytologic evidence of TCC or biopsy-confirmed TCC.58 The reported tumor responses included two (5%) CR, eight (21%) PR, and 19 (50%) SD. The median survival was 230 days. Other emerging therapies that have shown promise include singleagent vinblastine52 and metronomic chlorambucil.63 Thirty-six percent of dogs with TCC receiving vinblastine had partial remission.52

Localized Therapy  Localized therapies studied in dogs with

TCC include intravesical mitomycin C (MMC) and photodynamic therapy (PDT). Intravesical therapy is commonly used in humans with superficial TCC, and there has been interest in this approach to potentially treat the higher grade invasive TCC that occurs in dogs. A phase I clinical trial and pharmacokinetic (PK) study of intravesical MMC (1-hour dwell time/day, 2 consecutive days each month, escalating concentrations) was performed in dogs with TCC.57 Tumor response was assessed in 12 of 13 dogs, and responses included five PR and seven SD. The treatment was well tolerated in most dogs, and the maximum tolerated dose based on local toxicity (bladder irritation of 1 to 2 days duration) was 700 µg/mL (1-hour dwell time/day, 2 consecutive days/month). It was noted that care should be taken to prevent the drug from pooling in the prepuce as this could cause more severe irritation. Unfortunately, a much more serious toxicosis emerged. Marked myelosuppression and severe GI upset were noted in two dogs, suggesting that the drug had been absorbed systemically. This occurred after the first treatment cycle in one dog and the fourth cycle in another dog. Serum MMC concentrations were minimal in dogs that provided samples for PK analyses, but neither of the two dogs with severe toxicity had blood sampled for PK analyses. Although both dogs with severe toxicity recovered with supportive care, systemic exposure is of great concern. The amount of drug being instilled in the bladder is great enough that, if a substantial proportion of the drug were to be systemically absorbed, it could be lethal. Therefore intravesical

therapy is not recommended for initial management in dogs with TCC. If other drugs have failed and a given patient does not have other options, then the clinician and pet owner would need to carefully consider the risk versus potential benefit before deciding to use intravesical therapy. In the future, other intravesical therapies may emerge. Experimentally, paclitaxel gelatin nanoparticles have been delivered intravesically to dogs with TCC, but this approach is not in routine use.64 Another localized therapy studied in dogs with TCC is PDT.65-67 PDT with 5-aminolevulinic acid (ALA) had potent antiproliferative effects in canine TCC cells in vitro.65 ALA was given to healthy dogs, and induction of the photoactive metabolite, protoporphyrin IX (Pp IX), was confined to the bladder mucosa.66 In five dogs with TCC treated with ALA-based PDT, the progression-free interval ranged from 4 to 34 weeks (median was 6 weeks). ALA-based PDT was used in a male dog with urethral TCC, and this dog was still disease free 1 year after treatment.67

Supportive Care

Dogs with TCC are at high risk for secondary bacterial infections. Urine samples collected by free catch or catheter (to avoid potential seeding from cystocentesis) should be submitted for urinalyses and culture regularly and antibiotics prescribed as indicated. Urination should be monitored closely. If urinary tract obstruction occurs, catheterization, definitive anticancer therapy, antibiotics to reduce inflammation associated with secondary bacterial infection, or placement of stents or prepubic cystotomy tube may be pursued.

Prognosis

The progress being made to help dogs with TCC is encouraging. Multiple different treatments have been identified that result in remission or SD for several months, and the quality of life can be excellent. Unfortunately, most dogs with TCC still ultimately die of the disease. Survival has been strongly associated with the TNM stage at the time of diagnosis (Table 29-4). Factors associated with a more advanced TNM stage at diagnosis include younger age (increased risk of nodal metastasis), prostate involvement (increased risk of distant metastasis), and higher T stage (increased risk of nodal and distant metastasis).2 Information on the treatment and prognosis of other types of bladder cancer has been limited. Remission has been reported in a dog with bladder lymphoma treated with radiation and chemotherapy.6

• Table 29-4 TNM Stage at Diagnosis and Survival of 102 Dogs with Urinary Bladder Transitional Cell Carcinoma (TCC) Tumor Stage

T1 or T2 T3 N0 N1 M0 M1

Dogs (no.)

Median Survival (days)

82 20 86 16 88 14

218 118 234 70 203 105

Wilcoxon 2-Sample Test (p value)

0.0167 0.0001 0.0163

Modified from previous report by 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 5:47–59, 2000.

Chapter 29  Tumors of the Urinary System  579

Feline Urinary Bladder Tumors Bladder cancer is rarely reported in cats. A series of 27 feline bladder tumors included 15 carcinomas, 5 benign mesenchymal tumors, 5 malignant mesenchymal tumors, and 2 lymphomas.68 There were 20 male and 7 female cats, and most were elderly. Partial cystectomy was performed in 9 cats, and 4 cats (2 with leiomyoma, 1 with hemangiosarcoma, and 1 with leiomyosarcoma) survived longer than 6 months.68 A series of 20 cats with TCC has been reported, including 13 neutered male and 7 spayed female cats (median age 15.2 years).69 A series of 15 cats with TCC examined at the PUVTH in recent years included 6 neutered male and 9 spayed female cats (median age 13 years, range 4 to 18 years).70 Clinical signs in cats with TCC include hematuria, stranguria, and pollakiuria. Concurrent urinary tract infection is common, being reported in 75% of cats in the published study69 and 67% of cats at the PUVTH.70 Regional and distant metastasis of feline TCC is clearly possible, but the metastatic rate has not been defined. Of 20 cats with TCC in the published series, treatment was given to 14 cats and included surgery alone (2), surgery plus other therapy (8), piroxicam (3), and chemotherapy (1).69 The MST was 261 days.69 Due to the limited number of cats receiving each treatment, the value of specific treatments cannot be determined. In a case report, one cat with urethral TCC had surgical debulking, and recurrence was noted 316 days postoperative.71 This cat subsequently was treated with RT and died 70 days later.

Urethral Tumors Most urethral tumors are malignant epithelial tumors (TCC or squamous cell carcinoma), with smooth muscle tumors reported less frequently. It is important to distinguish urethral tumors from granulomatous urethritis because the treatment and prognosis differ. Although most urethral tumors are not resectable, long-term survival has been reported in a dog with multiple chondrosarcomas in the urethra following surgery.72 Urinary diversion techniques described under “surgery and nonsurgical procedures” of urinary bladder TCC could be considered. The response of urethral TCC to chemotherapy or piroxicam appears similar to that of TCC of the urinary bladder.49,59

Renal Tumors Tumors that have metastasized to the kidneys from other locations are more common than primary renal tumors, which comprise fewer than 2% of all canine cancers.73 Most primary renal tumors are malignant, and more than half of these are epithelial in origin. The most common renal tumor in dogs is renal cell carcinoma (RCC), accounting for 49% to 65% of primary tumors. Other tumors that can occur in the kidney include TCC, nephroblastoma, hemangiosarcoma, other sarcomas, and lymphomas (see Chapter 32, Section A).73-75 Lymphoma and RCC often occur bilaterally. RCC can be highly invasive into adjacent structures and may invade the vena cava. An unusual syndrome in German shepherd dogs consists of slow-growing dermal fibrosis and fibromas, concomitant renal cystadenocarcinoma, and uterine tumors in affected females.76 This syndrome results from a dominantly inherited missense mutation in folliculin, a putative tumor suppressor gene.77,78 This condition in dogs is thought to be similar to Birt-Hogg-Dubé syndrome in humans.77,78

Diagnosis and Clinical Staging

Most RCCs and sarcomas occur in older dogs (mean age 8 years), but nephroblastoma may occur at any age. The male : female ratio of dogs with epithelial renal tumors has been reported to be 1.2 : 1 to 1.6 : 1.73,74 Clinical signs in dogs with renal tumors are often nonspecific and may include anorexia, weight loss, polyuria, lethargy, or hematuria. Gross hematuria is not a consistent finding. Physical examination may reveal a palpable abdominal mass or, in some cases, pain in the region of the kidneys. Bone metastases or hypertrophic osteopathy is uncommon. Laboratory findings in dogs with renal tumors may include mild-to-moderate anemia or polycythemia from a suspected increased production of erythropoietin. Serum biochemical changes are nonspecific and can include azotemia, elevation in alkaline phosphatase, or hypoalbuminemia. Clinical staging of renal cancer should include radiography of the thorax and abdominal ultrasonography. Excretory urography, CT, and evaluation of glomerular filtration rate (GFR) via scintigraphy may also be useful, especially for surgical planning. Evaluation of possible tumor extension into the vena cava is important if surgery is considered. Histopathologic examination is required for diagnosis. Tumor tissue can be obtained by ultrasound-guided percutaneous biopsy or at surgery. Immunoreactivity to uromodulin, c-Kit, and vimentin has been reported in canine RCC.79 Immunohistochemical findings vary across subtypes of RCC. Papillary and tubulopapillary RCCs appear to express cytokeratins more often than solid RCCs.79

Treatment and Prognosis

Nephrectomy is the treatment of choice for dogs with unilateral renal tumors that have not metastasized. Surgery should include removal of the ureter and possibly retroperitoneal muscle and tissue if the tumor has extended through the capsule and invaded surrounding tissues. In 68 dogs with various renal tumors that underwent nephrectomy, the MST was 16 months.74 Renal lymphoma is generally treated with chemotherapy (see the section on Lymphoma in Chapter 32, Section A). Successful chemotherapy protocols for other forms of renal cancer have not been identified, and surgery remains the mainstay of treatment. Pulmonary metastases have been detected radiographically in 16% to 34% of dogs with primary renal tumors at the time of diagnosis.73,74 At death, metastases were detected in 69% of dogs with carcinomas, 88% of dogs with sarcomas, and 75% of dogs with nephroblastomas. Although the survival time for dogs with malignant renal tumors can be short, long-term survival (up to 5 years) in individual dogs has been observed. The median survival in a series of dogs with renal hemangiosarcoma was 278 days.80

Feline Renal Tumors Primary renal tumors in cats are rare.81 Of 19 cats with primary renal tumors, excluding lymphoma, the median age at diagnosis was 11 years, with similar numbers of male and female cats.81 The tumors were typically unilateral and included 11 tubular renal carcinoma, 2 tubulopapillary renal carcinomas, 3 TCCs, and 1 each of nephroblastoma, hemangiosarcoma, and adenoma. One cat had polycythemia. The majority of cats had metastases. In a case report involving two cats with renal adenocarcinoma and secondary polycythemia, the polycythemia resolved in both cats following nephrectomy.82

580  Part IV Specific Malignancies in the Small Animal Patient

Comparative Aspects

Transitional Cell Carcinoma

Urinary bladder cancer is newly diagnosed in more than 65,000 humans each year in the United States.83 Cigarette smoking is by far the most common known cause of human bladder cancer. In humans, more than two-thirds of bladder tumors are superficial low-grade tumors in the bladder mucosa.83 These tumors generally respond well to transurethral resection and intravesical therapy, although recurrence is common, and progression to invasive TCC is a risk. Approximately 20% of human bladder cancers are higher grade invasive TCC at the time of diagnosis. Metastasis to the regional lymph nodes, lungs, and other organs occurs in approximately 50% of cases of invasive TCC.83 More than 14,000 people die of bladder cancer each year in the United States, and most deaths are due to invasive, metastatic TCC.83 TCC in dogs is extremely similar to invasive TCC in humans in histopathologic characteristics; cellular and molecular features studied to date; biologic behavior, including metastasis; and response to therapy.1-3,21,84-90 Canine TCC has emerged as a highly relevant model for human invasive bladder cancer.2,3 Successful therapies in dogs have been translated into human clinical trials, and similar effects have been observed between both species.91

Renal Cancer

Major types of renal cancer in humans include RCC, TCC of the renal pelvis, and Wilms’ tumor (nephroblastoma), which is most commonly diagnosed in children.92,93 Renal cancer is newly diagnosed in 58,000 people and results in approximately 13,000 deaths each year in the United States. RCC accounts for 90% of adult renal carcinomas. Risk factors for RCC include cigarette smoking, obesity, and hypertension.92 Multiple subtypes of RCC exist, including clear cell, papillary, and chromophobe types. The clear cell type is associated with von Hippel-Lindau (VHL) disease in which mutations occur in the VHL gene. A small number of canine RCC samples have been studied for VHL gene mutations.94 Mutations were not identified, but this does not rule out mutations in other dogs.94 Metastases (lymph nodes, lung, bone, liver, others) are present at diagnosis in 30% of people with RCC. RCC in humans has been treated with surgery, radiation, chemotherapy, and biologic therapy (interferon and interleukin-2). Further study would be indicated to more fully examine the similarities and differences between canine and human RCC.

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