Tumors of the Urinary System

30

Tumors of the Urinary System CHRISTOPHER M. FULKERSON AND DEBORAH W. KNAPP

Canine Urinary Bladder Tumors

Etiology and Prevention

Urinary bladder cancer accounts for approximately 2% of all reported malignancies in the dog.1–3 With more than 65 million dogs in the United States, and the estimated 6 million new canine cancer cases in the United States each year, even less frequent forms of cancer, such as bladder cancer, affect tens of thousands of dogs each year.2,3 Invasive urothelial carcinoma (iUC), also referred to as invasive transitional cell carcinoma, is the most common form of canine urinary bladder cancer.1–3 Most iUCs are intermediate- to high-grade papillary infiltrative tumors.1–3 A series of 232 iUCs included 70% grade 3 (high grade) tumors, 29% grade 2 (intermediate grade) tumors, and 1% grade 1 (low grade) tumors.3 Other types of bladder tumors reported less frequently include squamous cell carcinoma, adenocarcinoma, undifferentiated carcinoma, rhabdomyosarcoma, lymphoma, hemangiosarcoma, fibroma, and other mesenchymal tumors.1–8 iUC is most often located in the trigone region of the bladder. Papillary lesions and a thickened bladder wall (Fig. 30.1) are common features, and can lead to partial or complete urinary tract obstruction. In a series of 102 dogs with iUC of the bladder, the cancer also involved the urethra in 56% of dogs and the prostate in 29% of male dogs.1 Nodal and distant metastases were present in 16% and 14% of dogs, respectively, at diagnosis.1 Following World Health Organization (WHO) criteria for staging canine bladder tumors (Box 30.1),9 78% of dogs had T2 tumors and 20% had T3 tumors.1 In a necropsy study of 137 dogs with iUC, 58% of dogs had distant metastases and 42% had nodal metastases (including 33% of dogs with both nodal and distant metastases).3 The lung was the most common site of distant metastases (50% of dogs), with other sites including liver, kidney, adrenal gland, spleen, bone, skin, heart, brain, and gastrointestinal (GI) tract.3 At necropsy, second primary tumors were noted in 13% of dogs, including hemangiosarcoma, lymphoma, thyroid carcinoma, and others.3 Bone metastases were reported in 17 (9%) of 188 canine iUC cases reviewed retrospectively, and in 3 (14%) of 21 dogs prospectively undergoing total body computed tomography (CT) at euthanasia followed by a standardized pathologic examination.10 In a series of 12 dogs with cutaneous iUC metastases, gross lesions consisted of plaques, papules, and nodules.11 iUC can occur in the abdominal wall, either through seeding from instruments and needles used in surgical and nonsurgical procedures, or through natural spread of transmural lesions along bladder ligaments.12 iUC in the abdominal wall is typically aggressive and poorly responsive to medical therapy.12

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 gender, and a very strong breed-associated risk (Table 30.1).1–3,13–15 The female-to-male ratio of dogs with TCC has been reported to range from 1.71:1 to 1.95:1, although the sex predilection is less pronounced in high-risk breeds.3 TCC risk is higher in neutered dogs than intact dogs of both genders, although the reason for this has not been determined.1–3,13 In a case control study of 166 Scottish terriers (STs), TCC risk was significantly higher in STs that had been exposed to lawn herbicides and insecticides than in dogs not exposed, and the risk was significantly lower in dogs that ate vegetables at least three times per week in addition to their dog food.14,16 The specific vegetable with the most benefit could not be determined, but carrots, given as treats, were the most frequently fed vegetable. In contrast to older types of flea dips, exposure to spot-on products containing fipronil was not associated with an increased TCC risk.15 It would appear appropriate to inform owners of dogs in high-risk breeds

* *

•

Fig. 30.1 Dog, urinary bladder. Urothelial (transitional cell) carcinoma. Transmural neoplastic growth involving the entire bladder (asterisk). One of the iliac lymph nodes (black circle) is also infiltrated by this neoplasm. One of the ureters is dilated (hydroureter, thin arrow) and the corresponding kidney (opened, thick arrow) has hydronephrosis as a result of blockage of the ureter at the trigone. (Courtesy J. A. Ramos-Vara, Purdue University.)

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of the risk, 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 at high risk for iUC. Urinary tract ultrasonography and urinalysis with sediment examination at 6-month intervals, plus cystoscopy and biopsy of suspicious lesions, has allowed detection of iUC in STs before the onset of clinical signs, and treatment response has been better than in more advanced iUC (D. Knapp, personal communication). Other screening tests for iUC are emerging. A BRAF V595E mutation has been detected in more than 80% of canine iUC cases with urine detection closely correlating to tumor tissue genotype.17,18 In one study, the BRAF V595E mutation was detected in 19 of 23 dogs presenting with iUC and in 0 of 37 dogs that were either normal or had cystitis.18 Copy number aberrations in urine DNA from dogs with iUC have also been reported.19 Screening strategies including these tests could help identify dogs for further evaluation for potential iUC.  • BOX 30.1  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 No regional lymph node involvement N1 Regional lymph node involved N2 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 tumors in domestic animals, Geneva, 1980, World Health Organization.9

Presentation, Diagnosis and Differential Diagnoses, and Clinical Staging Common clinical signs in dogs with iUC include hematuria, dysuria, pollakiuria, and less commonly lameness caused by bone metastasis or hypertrophic osteopathy.1 Urinary tract signs mimic those of dogs with urinary tract infections (UTIs) and may resolve temporarily with antibiotic therapy if a concurrent UTI is present. Concern for iUC or other urinary tract abnormalities, such as calculi, arise when clinical signs do not resolve with antibiotics or recur soon after a course of antibiotics is completed. In dogs with iUC, a physical examination, which includes a rectal examination, may reveal thickening of the urethra and trigone region of the bladder, enlargement of lymph nodes, prostatomegaly in male dogs, and sometimes a mass in the bladder or a distended bladder. However, a normal physical examination does not rule out iUC. Many conditions mimic iUC in regard to clinical signs, presence of abnormal epithelial cells in urine, and mass lesions within the urinary tract (Fig. 30.2 and 30.3). Differential diagnoses include other neoplasia, chronic bacterial cystitis, polypoid cystitis, fibroepithelial polyp, granulomatous cystitis/urethritis, gossypiboma, calculi, and inflammatory pseudotumor.4–8,20–22 It is important to differentiate non-iUC conditions from iUC because the treatments and prognosis differ considerably and are dependent on the condition present. A definitive diagnosis of iUC is made through histopathologic examination of tissues. Immunohistochemistry for uroplakin III and potentially GATA-3 can be used to determine urothelial origin of the cancer in difficult cases.3 Methods for obtaining tissue for histopathologic diagnosis include cystotomy, cystoscopy (Fig. 30.2), and traumatic catheterization.1,23 Cystoscopy provides the opportunity to visually inspect the urethra and bladder and to obtain biopsies via a noninvasive method. With the small size of cystoscopic biopsies, the operator must be diligent to collect sufficient tissue for diagnosis. Placing tissue samples in a histology cassette before processing helps prevent loss of small samples (Fig. 30.2F). The use of a wire basket designed to capture stones during cystoscopy (Fig. 30.2D, E) allows collection of larger samples. Traumatic catheterization to collect tissues for diagnosis can also be performed, although samples are usually small and the diagnostic quality is variable. Percutaneous biopsy methods can lead to tumor seeding and should be avoided.24

TABLE 30.1  Breed and Risk of Invasive Urothelial Carcinoma (iUC) in Pet Dogs3

Number of Dogs in That Breed in Database

TCC Cases in That Breed in Database

OR compared with mixed breed

95% confidence intervals

Mixed breed dog (Reference Category)

42,777

269

1.0

NA

Scottish terrier

670

79

21.12

16.23–27.49

Eskimo dog

225

9

6.58

3.34–12.96

Shetland sheepdog

2521

93

6.05

4.76–7.69

West Highland white terrier

1234

44

5.84

4.23–8.08

Keeshond

381

10

4.26

2.25–8.07

Samoyed

471

10

3.43

1.81–6.49

Beagle

3236

62

3.09

2.34–4.08

Dalmatian

1253

19

2.43

1.52–3.89

Breed

The odds ratios (ORs) of TCC risk compared with the risk in mixed breed dogs are included for breeds with an OR > 2.0 and at least 9 cases of iUC in the breed.

  

CHAPTER 30  Tumors of the Urinary System

In dogs with confirmed or suspected iUC, evaluation should include an assessment of overall health (complete blood count, serum biochemistry profile, urinalysis, ± urine culture) and staging of the cancer (three-view thoracic radiograps, abdominal ultrasonography or computed tomography [CT], and urinary

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tract imaging). To avoid the risk of seeding iUC through cystocentesis, urine may be collected by free catch or catheterization. Catheterization must be performed carefully to avoid penetrating the diseased bladder or urethral wall. Urinary tract imaging is used to assess the tumor location for potential surgical intervention

A

B

C

D

E

F

G

H

I

• Fig. 30.2  Images from cystoscopy of dogs with invasive urothelial carcinoma (iUC, A–E) and biopsy material

obtained (F), and images of dogs with polypoid cystitis (G–I). TCC can appear as a ruffled frond-like mass, a solid smooth mass, or as polyp-like lesions. High-quality images can be obtained with rigid cystoscopes typically used in female dogs (A, C–E) and in digital flexible scopes used in male dogs (B, image from a male Scottish terrier). The use of a cystoscopic wire stone basket (D, 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–I) appears very similar to TCC, but it is treated differently and has a better prognosis than TCC. Images (H) and (I) are from a dog with polypoid cystitis before (H) and after (I) a month of clavamox treatment alone with no other therapy. The polpys had regressed by more than 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 and D. W. Knapp, Purdue University.)

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and to map and measure iUC masses to subsequently determine response to therapy. Cystosonography, cystography, or CT may be employed.25–28 To accurately track response to therapy, regardless of the imaging approach, it is essential to follow a consistent protocol from visit to visit for imaging modality, bladder distention, patient positioning, and images acquired. When using cystosonography to monitor response, it is critical to have the same operator perform examinations over multiple visits. 

Treatment Localized Therapy Surgery

Surgery may be indicated to (1) obtain tissue for a definitive diagnosis, (2) eradicate lesions amenable to wide excision (e.g., tumors distant from the trigone), and (3) relieve urinary tract obstruction. Local recurrence after partial cystectomy and the presence of multifocal lesions within the bladder in many dogs with iUC support the notion of the field effect or malignant transformation of the entire urothelium in response to carcinogen exposure.29 Surgical removal of iUC is typically followed by systemic therapy, usually with a cyclooxygenase (COX) inhibitor, to reduce

risk of recurrence.1,29 When considering surgery, patient selection and owner counseling regarding risks (procedural risk, risk of recurrence) are essential. The risk of tumor seeding at the time of surgery is well documented and careful surgical technique is critical.12,29,30 Full-thickness removal of part of the bladder may be considered in dogs with discrete iUC lesions away from the trigone. In a retrospective study of 37 dogs with iUC treated with partial cystectomy (all gross tumor removal in 92% of dogs) plus COX inhibitors, with or without chemotherapy, the median progression-free interval (PFI) was 235 days, and the median survival time (MST) was 348 days.29 In a subset of 22 dogs treated with surgery and daily piroxicam (with or without other systemic therapy), the MST was 722 days.29 This result is similar to results in a series of nine dogs that had surgical resection of iUC (three dogs with tumor-free margins and six dogs with residual microscopic disease) followed by single-agent deracoxib, in which the MST was 749 days.1 More complex surgical approaches in dogs with iUC have also been reported including total cystectomy plus various urinary diversion strategies, but serious complications limit the success of these approaches.31–34 Prepubic cystostomy catheters or low-profile cystostomy tubes can be placed to bypass urethral

A

B

C

D • Fig. 30.3  Cystosonography images from dogs with bladder masses. Images made in the sagittal (A) and

transverse (B) planes (5 mL/kg fluid distention of the bladder) of an 11-year-old neutered male Shih Tzu with invasive urothelial carcinoma. To measure bladder masses over multiple time points, it is important to follow a consistent protocol in regard to level of bladder distention, and patient and probe positioning; and to have the same operator perform the ultrasonography on each visit. Polypoid cystitis (C, D), which can appear very similar to iUC, 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 and trigone areas of the bladder. Surgical biopsies of the masses confirmed they were polyps. (Courtesy J. F. Naughton, Purdue University.)

CHAPTER 30  Tumors of the Urinary System

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Radiation Therapy Although iUC cells are generally thought to be sensitive to radiation therapy (RT), an in vitro study of three canine iUC cell lines revealed a low α/β ratio, suggesting moderate radioresistance and supporting treatment protocols using higher doses and less fractionation.46 The early use of large doses and less fractionation, however, was associated with chronic colitis, cystitis, and urethral strictures, and little improvement in MST compared with medical therapy alone.47,48 With new advanced image-guided targeting technology and increasing availability of RT, there is renewed interest in RT to treat iUC.49–53 A retrospective report of intensity-modulated and imageguided radiation therapy revealed lower complication rates compared with earlier studies in the dog.49 In a series of 21 dogs, acute side effects were mild and self-limiting and included colitis (38%), erythema or hyperpigmentation (19%), and stranguria (5%).49 Late complications included urethral stricture (9%), ureteral stricture (5%), or rectal stricture (5%). The median event-free survival was 317 days and the overall MST was 654 days.49 In a report of 13 dogs with urogenital carcinomas treated with a low dose palliative RT (10 daily fractions of 2.7 Gy with CT planning) plus antineoplastic drugs, acute side effects were mild including colitis, cystitis, vaginitis, and dermatitis, and no late complications were noted.50 Complete remission (CR) or partial remission (PR) was reported in 61% of dogs and stable disease (SD) in 38% of dogs.50 

obstruction in a palliative setting or to maintain urine flow while other therapies are instituted.35–37 Complications can include urine leakage and tumor seeding, infection, tube displacement, and tube damage if the dog is allowed to chew on the tube.  Urethral and Ureteral Stent Placement and Laser Ablation

In recent years, the use of interventional radiology approaches has gained favor over tube cystostomy and other surgical procedures for palliative management of obstruction secondary to iUC.30,38–41 Most urethral stents and some ureteral stents can be placed with minimally invasive approaches, and stents do not require pet owners to manipulate a urine collection system. Survival after urethral and ureteral stent placement is variable and largely dependent on the extent of tumor lesions. In three reports, MSTs have ranged from 20 to 78 days (range, 2–536 days) after urethral stent placement for iUC or prostatic adenocarcinoma.39–41 After urethral stent placement, lower urinary tract signs, including stranguria, can persist. Incontinence has been reported in 25% to 39% of dogs.39–41 Urethral stents are typically placed using fluoroscopic guidance, but the use of digital radiography to guide stent placement has also been reported.42 Ureteral stents can be placed surgically, and in some cases, nonsurgically in dogs with iUC. The MST after ureteral stent placement was 57 days (range, 7–337 days) in one study.43 Nephrectomy can be considered for severe unilateral hydronephrosis if persistent renal pain or infection is present. Transurethral carbon dioxide (CO2) and near-infrared diode laser ablation of iUC (performed in combination with cytotoxic chemotherapy and COX inhibitors) has been reported, with its main application being in dogs with discrete tumor masses causing urinary tract obstruction.44,45 Complications include perforation with iUC spread, transient postprocedural worsening of stranguria and hematuria, urethral stenosis, and infection.44,45 In a small series, the outcome of dogs treated with laser ablation and medical therapy was not better than medical therapy alone.44 

Medical Therapy Systemic Medical Therapy

Systemic medical therapy is the mainstay of  iUC treatment in dogs, and usually consists of chemotherapy, COX inhibitors (nonselective and COX-2 selective inhibitors), and combinations thereof (Table 30.2).1–3,27,54–62 Although medical therapy is not usually curative, several different drugs lead to remission or SD of iUC, and most therapies are well tolerated. Resistance to one drug does not imply resistance to other drugs. Some of the best results are seen in dogs

TABLE 30.2  Study Results Reported for the Medical Therapy of Invasive Urothelial Carcinoma (iUC) in Dogs

Number of Dogs: Total/Evaluable for Tumor Response

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

CR (%) PR (%)

SD (%)

PD (%)

PFI (d)

Median Survival From Start of That Drug(s) Refs.

Vinblastine (2.5 mg/m2)a

27/26

4/7/11

0

22

70

4

143

531b

59

mg/m2)/

24/24

0/4/4

0

58

33

8

199

299

59

8/8

12/12/12

0

0

50

50

84

300c

1–3

mg/m2)/

Cisplatin (60 piroxicama,d

14/14

28/14/43

14

57

28

0

124

246

1–3

Cisplatin (60 mg/m2)a

15 /14

20 /20 /33

0

13

53

27

87

338e

62

15/12

33/27/53

0

20

33

27

105

152

62

Cisplatin (60 coxib (5 mg/kg)a

14/11

21/14/29

0

57

21

0

186

179

62

Mitoxantrone/piroxicamf

26/NA

8/NA/8

0

8

69

23

106

247

56

Carobplatin/piroxicamf

24/NA

29/NA/29

0

13

54

33

73

263

Drug(s) Randomized Trials Vinblastine (2.5 piroxicama

Cisplatin (60 mg/m2)a

Firocoxib (5

mg/kg)a mg/m2/firo-

56 Continued

PA RT I V     Specific Malignancies in the Small Animal Patient

650

TABLE 30.2  Study Results Reported for the Medical Therapy of Invasive Urothelial Carcinoma (iUC) in Dogs—cont’d

Number of Dogs: Total/Evaluable for Tumor Response

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

CR (%) PR (%)

SD (%)

PD (%)

PFI (d)

Median Survival From Start of That Drug(s) Refs.

Piroxicama

94/76

9/11/16

3

18

59

20

120

244

3

Deracoxiba

26/24

4/11/15

0

17

71

12

133

323

54

Vinblastinea,g,h

28/28

11/21/28

0

36

50

14

122

147

58

Vinblastine–folate conjugatea

10/9

10/40/40

0

56

44

0

58

115

66

Vinblastine/toceranib/COX inhibitorf

10/9

20/0/20

0

33–55i

NA

NA

NA

NA

27

Mitoxantrone/piroxicamf

55/48

NA/NA/11

2

33

46

19

194

291

1

Carboplatina

14/12

21/14/28

0

0

8

92

41

132

1

Carboplatin/piroxicama

31/29

13/13/19

0

38

45

17

NA

161

1

Doxorubicin/piroxicamf

34/23

NA/NA/NA

0

9

60

30

103

168

55

Gemcitabine/piroxicamf

38/37

11/3/11

5

22

51

22

NA

230

57

Cisplatin (60 mg/m2)a

18/16

NA/28/33

0

19

25

56

75

130

1–3

Cisplatin (40–50 mg/m2)a

14/14

7/7/7

0

7

36

57

78

307

1–3

Cisplatin (60 mg/m2)/ piroxicama

14/12

14/14/28

0

50

17

33

NA

329

1–3

Cisplatin (60 mg/m2/ piroxicam/tavoceptf

14/11

NA/NA/NA

0

27

73

0

NA

253

60

Chlorambucil (4 mg/m2 daily)a

30/30

10/30/33

0

3

67

30

119

221

61

5-Azacitidinea

19/18

5/15/15

0

22

50

22

NA

203

67

Mitomycin C—intravesicala

13/12

0/0/0

0

42

58

0

120

223

69

Drug(s) Single-Arm Trials

aDiagnosis

based on histopathology.

bWhen

dogs receiving vinblastine alone failed, there was then the option for the dogs to receive piroxicam alone or other drugs. Twenty dogs received piroxicam alone after failing vinblastine alone. The responses to piroxicam were 3 (15%) PR, 9 (45%) SD, 5 (25%) PD, and 3 (15%) NA. Twelve of these dogs received additional therapy after failing piroxicam. In the combined therapy arm, 15 dogs received additional therapy after failing vinblastine/piroxicam. cDogs

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 could have contributed to the favorable survival in that treatment arm. dDespite

favorable tumor response, the combination of cisplatin and piroxicam is not recommended for routine use because of frequent renal toxicity.

eAfter

failing cisplatin alone, options were given for the dogs to receive firocoxib alone or other drugs. Thirteen dogs received firocoxib alone after failing cisplatin alone, and tumor responses included 2 PR, 4 SD, and 7 PD. This (and other drugs) could have contributed to the longer survival time. fStudy

included dogs with cytologic evidence of TCC and dogs with biopsy-proven TCC.

hThe

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. The currently recommended starting dosage of vinblastine for dogs with iUC is 2.5 mg/m2 every 2 weeks for medium to large dogs and 2.0 mg/ m2 every 2 weeks for small dogs with subsequent dose escalation in the absence of toxicity. iSeventeen jIn

of the dogs had failed a COX inhibitor before enrolling in the trial and continued to receive the COX inhibitor during the vinblastine treatment.

the study, the tumor masses were measured by ultrasound and by computed tomography. At 8 weeks, two different ultrasound operators reported tumor responses of 33% and 55% respectively.

More advanced TNM stage is associated with a poorer prognosis; the percentages of dogs with metastasis for each study are included. CR, Complete remission; NA, information not available; PD, progressive disease; PFI, progression-free interval; PR, partial remission; SD, stable disease.

  

that sequentially receive multiple different treatment protocols over the course of their disease. Baseline measurements of the iUC masses are obtained, an initial treatment protocol is instituted, and the iUC masses remeasured at 4- to 8-week intervals. The initial treatment is continued as long as the iUC is controlled (PR, SD), side effects are acceptable, and quality of life is good. Clinical signs do not consistently follow changes in tumor size with therapy; thus remeasuring the tumor is essential. If cancer progression or unacceptable toxicity occurs, then a different treatment is instituted.

Subsequent treatment changes are based on change in tumor size and treatment tolerability. With this approach, iUC growth can be controlled in approximately 75% to 80% of dogs, quality of life is usually very good, and MSTs have extended well beyond a year.1–3 Simultaneously combining multiple chemotherapy agents in dogs with iUC is not currently recommended because the benefit has not been determined, toxicity is likely to increase, and the potential development of resistance to multiple drugs at the same time could limit the options for subsequent therapy.

CHAPTER 30  Tumors of the Urinary System

The optimal length of chemotherapy for iUC has not been defined. Although the authors continue a chemotherapy protocol as long as the cancer is controlled, quality of life is good, and no serious adverse events are noted, other oncologists cap the number of chemotherapy doses because of concerns of chronic toxicity. The effects of discontinuing chemotherapy in dogs with PR or SD, or administering COX inhibitors or metronomic chemotherapy as “maintenance therapy,” have not been determined. It is certainly expected that residual iUC will progress if drugs controlling it are withdrawn. Anecdotally, the authors have administered vinblastine or mitoxantrone for well beyond a year without ill effects (D. Knapp, personal communication), but further study is needed. Systemic chemotherapy agents investigated in dogs with iUC are summarized in Table 30.2.1–3,48,55–62 Although cisplatin appears to be one of the more active agents, it is seldom used because of renal, GI, and bone marrow toxicities.1–3,60,62 In a recent report, the administration of cisplatin and piroxicam concurrently with a chemoprotectant agent (Tavocept) was associated with less renal toxicity than a historic control group receiving similar doses of cisplatin and piroxicam, but the response rate was inferior in the dogs that received Tavocept.60 In recent years, vinblastine has emerged as a preferred chemotherapy agent in dogs with iUC because of very good antitumor activity and a good safety profile.58,59 After promising results in a single arm trial in dogs with advanced resistant iUC, a follow-up trial was performed in which dogs with histologically diagnosed iUC were randomly assigned to receive vinblastine (2.5 mg/m2 intravenously every 2 weeks) plus piroxicam (0.3 mg/kg daily PO) or vinblastine alone (same dose).59 Remission was more frequent with vinblastine–piroxicam (58%) than with vinblastine alone (22%). The median PFI was 143 days with vinblastine alone and 199 days with the combination. Interestingly, the MST was significantly longer in dogs receiving vinblastine alone followed by piroxicam alone (531 days) than in dogs receiving the two drugs given concurrently (299 days). The longer survival was possibly due to the dogs not developing resistance to both drugs simultaneously. The treatment was well tolerated in both arms. Therefore vinblastine combined with piroxicam (or another COX inhibitor) has become the preferred chemotherapy protocol at the authors’ institution. Another commonly used chemotherapy protocol, mitoxantrone combined with piroxicam, induced remission in 35% of dogs with iUC with a MST was 291 days.1 Carboplatin combined with piroxicam induced remission in 38% of dogs, but is usually reserved for later use because of more frequent side effects.1 Other chemotherapy studies are summarized in Table 30.2. Low-dose frequent (metronomic) chemotherapy has also been used in dogs with iUC.61 A clinical trial of metronomic oral chlorambucil (4 mg/m2 daily) was performed in 31 dogs with iUC, 29 of which had failed prior therapy.61 Tumor responses included PR in one dog (3%) and SD in 20 dogs (67%). The median PFI and MST from the start of chlorambucil was 119 days and 221 days, respectively. The quality of life was excellent. Although toxicity was minimal in this study, with increased use of chlorambucil, especially for several months in dogs, chronic myelosuppression persisting for weeks to months has emerged as a concern. The chlorambucil dose used in the iUC trial (4 mg/m2 daily) was selected because it was more effective than lower or less frequent doses in early work.63 In a recent study, three different doses of chlorambucil (4 mg/m2, 6 mg/m2, or 8 mg/m2) were given to 78 dogs with a variety of cancer types.64 Doses greater than 4 mg/m2 were associated with more GI and bone marrow toxicity, but no improvement in antitumor effects. Of 34 dogs receiving 4 mg/m2,

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bone marrow suppression was noted in 10% of dogs at 90 days and in 80% of dogs at 1 year. Most toxicity was grade 1 or 2, but this justifies the need for careful monitoring. A more conservative treatment for iUC is a single-agent COX inhibitor, including the nonselective COX inhibitor piroxicam or COX-2 selective inhibitors such as deracoxib and firocoxib.1,3,54,62 All three of these agents have induced remission (with most being PRs) in 15 to 20% of dogs with iUC, and have resulted in SD in up to 55% of dogs. Information on 94 dogs with iUC treated with piroxicam (0.3 mg/kg daily) has been published.3 Tumor responses were known in 76 dogs and included 3% CR, 18% PR, 59% SD, and 20% PD. The median PFI was 120 days, and MST was 244 days.3 The MST 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).3 GI adverse events (due to piroxicam or comorbid conditions) were noted in 31% of dogs.3 Although most were grade 1 or 2, piroxicam can cause GI ulceration. It is critical for pet owners to observe their dog, stop piroxicam, and contact their veterinarian if anorexia, vomiting, or melena occurs. If the clinical signs are thought to be piroxicam related, it is safest to give a drug holiday and then switch to a COX-2 inhibitor. Interestingly, in an expanded series of dogs with multiple types of cancer receiving piroxicam, the use of GI-protectant drugs was associated with greater GI toxicity, but the reasons for this require further study.65 Although piroxicam can cause toxicity, the majority of dogs have notably improved quality of life on the drug.3 COX-2 selective inhibitors are also used in dogs with iUC. In a randomized trial, firocoxib (Previcox, Merial) had antitumor activity as a single agent (20% PR and 33% SD) and greatly enhanced the activity of cisplatin.62 Firocoxib did not worsen the renal toxicity of cisplatin (as piroxicam does), but other toxicities inherent to cisplatin still limit its use. In a clinical trial of singleagent deracoxib (Deramaxx, Novartis, 3 mg/kg PO daily) in 26 dogs with iUC, tumor responses included 17% PR, 71% SD, and 12% PD.54 The MST after deracoxib and subsequent therapies was 323 days. Mild GI toxicity occurred in 20% of dogs. Targeted therapies are also receiving considerable interest in treating TCC and other cancers in dogs. Folate-targeted vinblastine (EC0905, Endocyte) and the BRAF targeted drug vemurafenib have shown good promise in iUC (D. Knapp, personal communication).66 Toceranib combined with vinblastine and COX inhibitor has been studied, although responses did not appear better than for other vinblastine protocols.27 The injectable demethylating agent 5-azacitidine resulted in PR in 22% and SD in 50% of treated dogs.67 The pharmacokinetics, toxicity, and dosing of the oral demethylating agent zebularine in dogs with iUC have been reported, and a phase II trial is in progress (C. Fulkerson, personal communication).68  Localized Drug Delivery

The use of localized drug delivery in dogs with iUC has been limited, but has included intravesical mitomycin C and photodynamic therapy (PDT).69,70 Both have shown promise, but neither is used to any extent owing to the risk for systemic toxicity (when drugs instilled enter the circulation via vascularized tumors), local irritation to the bladder, and initial inflammation and tissue swelling after PDT.69,70 

Urinary Tract Infections The risk of urinary tract infections (UTIs) is high in dogs with iUC, especially in female dogs with urethral disease.71,72 This is due at least in part to urine retention, acquired structural defects

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in the bladder and urethra, damaged urothelium, and, in some cases, potentially compromised immune function.71,72 UTIs are problematic because they can result in worsening clinical signs, the false impression of cancer progression, and further malignant transformation, invasion, and metastasis secondary to inflammation.73–75 Antibiotic use can negatively affect the immune response through changes in the microbiome and other mechanisms.73 Another major problem with UTIs is the increasing resistance to antibiotics.71,76–79 For example, between January 2013 and February 2015, 168 resistant bacterial isolates from urine were reported at the Purdue University Veterinary Teaching Hospital, and 60% of the resistant isolates were from dogs with TCC (Fulkerson, unpublished data). In a 1-year period, 7 of 57 dogs with iUC developed infections that were sensitive only to nephrotoxic antibiotics, very expensive antibiotics, or were not sensitive to any antibiotics tested.1 These issues point out the need to appropriately treat UTIs, but to also refrain from prescribing antibiotics when not indicated, as this can promote antibiotic resistance. A positive urine culture, especially with a low colony count in the absence of worsening clinical signs and supporting findings on urinalysis, is not an indication to treat with antibiotics. If a dog with iUC develops new or progressive lower urinary tract signs, a urinalysis with sediment evaluation should be performed. If the urinalysis reveals pyuria or the presence of intracellular bacteria, a urine culture is recommended. Because of the risk of tumor seeding, urine samples for culture are collected via midstream voiding or through a urinary catheter. While waiting on culture results, an initial antimicrobial choice should target Escherichia coli and Staphylococcus spp., which are among the most common uropathogens in non–tumor-bearing and tumor-bearing dogs with UTIs.72 The authors typically prescribe amoxicillin–clavulanate or trimethoprim–sulfa pending culture results. Amoxicillin, doxycycline, and enrofloxacin (but not amoxicillinclavulanate or cephalexin) have been associated with resistance patterns in cultures performed within 30 days after use.80 The benefits and risk of other approaches to treat or control UTIs, such as methenamine maleate or bacterial transfer, have not yet been determined.81,82 

Prognosis Although iUC is not usually curable in dogs, it is considered very treatable because of the 75% chance of cancer control or remission with treatment. The quality of life in most dogs is excellent. Survival has been strongly associated with the TNM stage at the time of diagnosis.1,3 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).1,3 

Feline Urinary Bladder Tumors Bladder cancer is rarely reported in cats. iUC is the most frequently reported form of feline bladder cancer, with mesenchymal tumors, lymphoma, and other tumors being less common.83–89 Clinical signs of  iUC in the cat are similar to those in the dog.84 In contrast to dogs, more than half of iUCs in a series of 20 cats were away from the trigone.84 Cats in this series were treated with surgery, cytotoxic chemotherapy, COX inhibitors, or combinations thereof, and the MST was 261 days.84 As in canine and human iUC, most feline iUCs express COX-1 and COX-2.89 The MST of 11 cats treated with meloxicam was 311 days.89 The optimal drugs

for feline iUC and possible role of RT requires more study. Surgical approaches and the placement of stents and cystostomy tubes to improve urine flow have been reported in cats with iUC.35,90–92 

Canine Urethral Tumors Most urethral tumors in dogs are malignant epithelial tumors including iUC and squamous cell carcinoma, with other cancers being less common.93 Staging procedures and treatment recommendations for urethral iUC are generally the same as for iUC located in the bladder. It is important to note that granulomatous/chronic active urethritis comprised 24% of urethral lesions in a series of 41 dogs, and the clinical signs and lesions associated with granulomatous urethritis can mimic iUC.93 Complete urethral obstruction has been reported with granulomatous urethritis. Histopathology is particularly important for urethral masses to rule out granulomatous urethritis, as treatment and prognosis differ from those of iUC.93 

Canine Renal Tumors Canine renal cancer includes renal cell carcinoma (RCC), adenocarcinomas, iUC, papillary cystadenocarcinomas, and less commonly, sarcomas.94–97 Nodular dermatofibrosis in association with renal cystadenocarcinoma and uterine tumors has been reported, mostly in German shepherd dogs.98,99 This condition arises as a result of a dominantly inherited missense mutation in FLCN, a tumor suppressor gene coding for the protein folliculin, and is similar to Birt–Hogg–Dubé syndrome in people.98,99 Epithelial renal tumors and sarcomas tend to occur in older dogs.94 Nephroblastoma has been reported in young dogs (including a 3-month-old dog), middle-aged, and older dogs.94–96 A male predisposition has been reported.97 Clinical signs, when present, include hematuria, pain in the area of the kidneys, a palpable abdominal mass, bone pain secondary to hypertrophic osteopathy, or other nonspecific signs such as GI upset or behavior changes.94–96,100 Laboratory findings can include mild to moderate anemia, neutrophilia, azotemia, elevated alkaline phosphatase, hypoalbuminemia, hypercalcemia, and paraneoplastic polycythemia secondary to erythropoietin production.94,101–104 In a case report of a dog with renal carcinoma and suspected paraneoplastic leukocytosis, immunohistochemistry revealed expression of granulocytemacrophage colony-stimulating factor by the tumor.103 Clinical staging should include thoracic and abdominal imaging. Tumor extension into the caudal vena cava is possible; thus CT may be useful for surgical planning. Evaluation of glomerular filtration rate via scintigraphy can also be useful. Histopathology is required for a definitive diagnosis and can be obtained by ultrasound-guided percutaneous biopsy or at the time of nephrectomy. Immunohistochemistry can help differentiate subtypes of RCC.105 Nephrectomy remains the treatment of choice for dogs with unilateral renal tumors with no evidence of metastasis and normal renal function. Even in dogs with metastasis, surgery can be palliative. Renal lymphoma is typically treated with chemotherapy (see Chapter 33), but effective chemotherapy protocols have yet to be described for most primary renal tumors. In one study, the MSTs were 16 months for 49 dogs with renal carcinomas, 9 months for 28 dogs with renal sarcomas, and 6 months for 5 dogs with nephroblastomas.94 Higher mitotic index, increased COX-2 expression, specific histologic subtypes, and Fuhrman nuclear grade have reported negative prognostic value for RCCs.106,107 The MSTs for dogs with a mitotic index of <10, 10 to 30, and >30 were 1184 days, 452 days, and 187 days,

CHAPTER 30  Tumors of the Urinary System

respectively.106 The MST appears shorter for clear cell (87 days) versus chromophobe, papillary, and multilocular cystic RCCs.106 Fuhrman nuclear grade, a human RCC histologic grading scheme based on morphologic features of nuclei and nucleoli, was prognostic in one study of 70 dogs with RCC with MSTs not reached, 1065 days, 379 days, and 87 days in dogs with grade 1, 2, 3, and 4 RCCs, respectively.106 Radiographic evidence of metastasis is present in 16% to 34% of dogs with primary renal tumors.94,97 Metastasis at death was reported in 88% of dogs with sarcomas, 75% with nephroblastomas, and 69% with carcinomas.94 

Feline Renal Tumors Primary renal tumors are rare in the cat. Excluding lymphoma, reported feline primary renal tumors include tubular RCC, tubulopapillary RCC, sarcomatoid RCC, adenocarcinoma, adenoma, iUC, squamous cell carcinoma, leiomyosarcoma, nephroblastoma, and hemangiosarcoma.108–115 The tubular and tubulopapillary RCC were most common in a series of 19 cats.108 The most common presenting complaint was weight loss. Metastasis was frequently detected at the time of diagnosis.108 Polycythemia has been reported in cats with primary renal tumors.108,115 In two cats with renal adenocarcinoma, polycythemia resolved after nephrectomy.115 Hypertrophic osteopathy has been reported in a cat with renal adenoma.110 In contrast to canine and human RCC, immunohistochemistry did not correlate with RCC subtype in a small series of cats.114 Nephrectomy could be considered in unilateral cancer. The role of chemotherapy is undefined. Limited information on survival is present, but most reports are associated with short survival times. 

Comparative Aspects Invasive Urothelial Carcinoma There are more than 65,000 new cases and more than 16,000 deaths from urinary bladder cancer in the United States each year, with most deaths from iUC.116 Cigarette smoking is by far the most common cause of human bladder cancer.116 In humans, more than two-thirds of bladder tumors are superficial low-grade non–muscleinvasive tumors.116 These tumors generally respond well to transurethral resection and intravesical therapy, although recurrence is common and progression to iUC is a risk. Approximately 20% of human bladder cancers are higher grade muscle-invasive urothelial carcinoma at the time of diagnosis. Metastasis to the regional lymph nodes, lungs, and other organs occurs in approximately 50% of human iUC cases.116 iUC in dogs is very similar to iUC in humans in histopathologic characteristics, cellular features, biologic behavior including metastasis, and response to therapy.2,3,116–125 Canine iUC has emerged as a highly relevant naturally occurring model for human invasive bladder cancer.2,3 Successful therapies in dogs have been translated into human clinical trials, and similar effects observed between the two species.2,3,126 Molecular analyses have further strengthened the role of canine TCC as a model for human iUC.127–134 In microarray and RNA-seq analyses, hundreds of genes that are differentially expressed between normal bladder tissues and iUC have been found that are shared between dogs and humans.127,128 Altered expression of genes shared between canine and human iUC includes COX-2, EGFR, HER2, p53 family genes, DNMT1, and VIM.121–125,129–133 The BRAF V595E mutation, which is present in 80% of canine iUC, leads to continuous activation of the MAPK pathway.17 This mutation is the canine homolog

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of the BRAFV600E mutation that drives 8% of all human cancer. Although BRAF mutations are rare in human iUC, other molecular variants are present that turn on the MAPK pathway in approximately 30% of human iUC cases.133 Mutations in several other genes implicated in the development and progression of iUC and other cancers in humans have been identified in canine iUC including EGFR, CDKN2B, PIK 3CA, BRCA2, NFκB, ARHGEF4, XPA, NCOA4, MDC1, UBR5, RB1CC1, RPS6, CIITA, MITF, and WT1.17,128,133 Another intriguing finding in canine iUC is the presence of molecular subtypes defined by gene signatures including luminal and basal subtypes initially observed in human breast cancer and then found in human iUC.127,134 This is important because cancer behavior, treatment response, and prognosis differ between subtypes in humans.134 

Renal Cancer Major types of renal cancer in humans include RCC, urothelial carcinoma of the renal pelvis, and Wilms’ tumor (nephroblastoma), which is most commonly diagnosed in children.135 Renal cancer is newly diagnosed in 64,000 people and results in 15,000 deaths each year in the United States. RCC accounts for 90% of adult renal carcinomas.135 Risk factors for RCC include cigarette smoking, obesity, and hypertension.136 Multiple subtypes of RCC exist including clear cell, papillary types I and II, and chromophobe types. The clear cell type can be sporadic or associated with von Hippel–Lindau disease in which mutations occur in the VHL gene. With recent progress in targeted and immunotherapies, the outlook for human RCC has improved substantially in recent years.

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12. Higuchi T, Burcham GN, Childress MO, et al.: Characterization and treatment of transitional cell carcinoma of the abdominal wall in dogs: 24 cases (1985-2010), J Am Vet Med Assoc 242:499–506, 2013. 13. Bryan JN, Keeler MR, Henry CJ, et  al.: A population study of neutering status as a risk factor for canine prostate cancer, Prostate 67:1174–1181, 2007. 14. 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 224:1290–1297, 2004. 15. 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 225:389–394, 2004. 16. 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. 17. Decker B, Parker HG, Dhawan D, et al.: Homologous mutation to human BRAF V600E is common in naturally occurring canine bladder cancer, evidence for a relevant model system and urinebased diagnostic test, Mol Cancer Res 13:993–1002, 2015. 18. Mochizuki H, Shapiro SG, Breen M: Detection of BRAF mutation in urine DNA as a molecular diagnostic for canine urothelial and prostatic carcinoma, Scarpa A, ed PLoS One 10:e0144170, 2015. 19. Mochizuki H, Shapiro SG, Breen M: Detection of copy number imbalance in canine urothelial carcinoma with droplet digital polymerase chain reaction, Vet Pathol 53:764–772, 2016. 20. Deschamps J-Y, Roux FA: Extravesical textiloma (gossypiboma) mimicking a bladder tumor in a dog, J Am Anim Hosp Assoc 45:89– 92, 2009. 21. Böhme B, Ngendahayo P, Hamaide A, et al.: Inflammatory pseudotumours of the urinary bladder in dogs resembling human myofibroblastic tumours: a report of eight cases and comparative pathology, Vet J 183:89–94, 2010. 22. Martinez I, Mattoon JS, Eaton KA, et al.: Polypoid cystitis in 17 dogs (1978-2001), J Vet Intern Med 17:499–509, 2003. 23. Childress MO, Adams LG, Ramos-Vara J, et  al.: Comparison of cystoscopy vs surgery in obtaining diagnostic biopsy specimens from dogs with transitional cell carcinoma of the urinary bladder and urethra, J Am Vet Med Assoc 239:350–356, 2011. 24. 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 149:314–318, 2007. 25. Hume C, Seiler G, Porat-Mosenco Y, et al.: Cystosonographic measurements of canine bladder tumours, Vet Comp Oncol 8:122–126, 2010. 26. Honkisz SI, Naughton JF, Weng HY: Evaluation of two-dimensional ultrasonography and computed tomography in the mapping and measuring of canine urinary bladder tumors, Vet J 232:23–26, 2018. 27. Rippy SB, Gardner HL, Nguyen SM, et al.: A pilot study of toceranib/vinblastine therapy for canine transitional cell carcinoma, BMC Vet Res 257(12), 2016. 28. Naughton JF, Widmer WR, Constable PD, et  al.: Accuracy of three-dimensional and two-dimensional ultrasonography for measurement of tumor volume in dogs with transitional cell carcinoma of the urinary bladder, Am J Vet Res 73:1919–1924, 2012. 29. Marvel SJ, Seguin B, Dailey DD, Thamm DH: Clinical outcome of partial cystectomy for transitional cell carcinoma of the canine bladder, Vet Comp Oncol 15:1417–1427, 2017. 30. Hosoya K, Takagi S, Okumura M: Iatrogenic tumor seeding after ureteral stenting in a dog with urothelial carcinoma, J Am Anim Hosp Assoc 49:262–266, 2013. 31. Saeki K, Fujita A, Fujita N, et al.: Total cystectomy and subsequent urinary diversion to the prepuce or vagina in dogs with transitional cell carcinoma of the trigone area: a report of 10 cases (2005-2011), Can Vet J 56:73–80, 2015.

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CHAPTER 30  Tumors of the Urinary System

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