GENERAL CONSIDERATIONS


Pathophysiology

•risk factors for TCC in dogs include:

•obesity

•aromatic amino metabolites of tryptophan (especially ortho-aminophenol) and oral 2-naphthylamine

•industrial environments

•exposure to marshlands sprayed with insecticides

•exposure to lawns or gardens treated with both herbicides and insecticides and herbicides alone, but not insecticides alone

•exposure to lawns or gardens treated with phenoxy herbicides, but not non-phenoxy herbicides

•exposure to topical insecticides for flea and tick control, but not more recent topical spot-on flea and tick products containing fipronil or imidacloprid

•± oral cyclophosphamide

•smoking is a major causative factor in humans with TCC

•dogs excrete large quantities of tryptophan metabolites in the urine

•however, cats metabolize tryptophan differently and do not excrete urinary tryptophan metabolites

•COX-2 is not expressed by normal urinary bladder epithelium, but is expressed in primary and metastatic bladder tumors in dogs

•COX-2 overexpression increases the invasive ability of tumor cells by activating MMP, increasing pro-angiogenic factors (i.e., VEGF), and decreasing E-cadherin (which are all important for tumor growth, invasion, and metastasis)


Signalment

•sex predisposition: female with a male-to-female ratio of 1:1.7

•breed predisposition: Scottish Terrier ± Beagle, Shetland Sheepdog, Wirehaired Fox Terrier, and West Highland White Terrier


Location

•TCC are most frequently located in the trigonal area in dogs resulting in urinary tract obstruction


Clinical Stage

•clinical staging of bladder tumors provides pertinent information on treatment options and prognosis

•T2 and T3 lesions are the most common in dogs, with:

•82%-98% invading the muscle layers of the urinary bladder wall

•56% involve the urethra and 29% involve the prostate




























Tumor Grade

•TCC is histologically graded according to the depth of invasion and degree of cellular differentiation

•grade 1 is well differentiated, grade 2 moderately differentiated, and grade 3 is anaplastic

•grade 2 lesions are the most common in dogs accounting for 57%-81% of TCC cases


Metastatic Disease

•metastatic disease correlates with the depth of bladder wall invasion (i.e., clinical stage)

•metastatic routes include direct extension into adjacent fat or regional organs, implantation into the peritoneal cavity, or lymphatic and hematogenous spread

•metastatic sites include regional and distant lymph nodes, lungs, genitourinary tract (i.e., urethra, ureter, kidneys, uterus, prostate, ovary, vagina, and mammary glands), GI (i.e., salivary glands, esophagus, liver, and intestines), endocrine glands (i.e., thyroid, adrenal, and pancreas), CNS (i.e., brain, spinal cord, and eyes), cardiovascular (i.e., aorta, heart, and pericardium), bone (i.e., rib, vertebrae, humerus, femur, and skull), and others such as the spleen, abdominal wall, and diaphragm

•16% metastatic rate to regional lymph node and 14% metastatic rate to distant sites at diagnosis

•48% metastatic rate to regional lymph node and 51% metastatic rate to distant sites at necropsy



DIAGNOSIS


Clinical Signs

•dysuria (84%), hematuria (50%), pollakiuria (37%), and stranguria

•vaginal discharge

•urinary obstruction

•incontinence

•lameness may be caused by either skeletal metastases or hypertrophic osteopathy (4%-10%)


Urinalysis and Urine Sediment Cytology


General Considerations

•hematuria and proteinuria are consistent findings on urinalysis due to ulceration of the urothelial mucosa

•bacteruria, pyuria, and positive urine cultures are common in cats

•bladder wash cytology may improve diagnosis capabilities by reducing contaminants


Urine Sediment Cytology

•neoplastic transitional cells are difficult to differentiate from reactive transitional cells

•urine sediment cytology successful in 30% of canine TCC

•30% of all TCC and 90% of muscle-invasive TCC are diagnosed with urine sediment cytology

•mesenchymal tumors exfoliate poorly and are rarely diagnosed with analysis of urine sediment




Blood Tests

•hematology and serum biochemistry findings are usually normal or non-specific

•mild to moderate normochromic, normocytic anemia can be caused by either hematuria or bone marrow suppression secondary to chronic disease

•uremia may result from neoplastic obstruction of urinary outflow or age-related renal failure


Imaging Studies


Survey Radiographs

•imagining techniques include survey abdominal and thoracic radiographs, contrast radiography, and CT

•survey radiographs: sublumbar lymph node enlargement, renomegaly, and metastatic disease in the pulmonary parenchyma or skeleton, particularly lumbar vertebrae and pelvis

•pulmonary metastasis with urinary TCC has 4 radiographic patterns:

•diffuse unstructured increase in interstitial density which can mimic old age changes

•localized interstitial or alveolar infiltrates

•multiple interstitial nodules

•normal pulmonary opacities

•positive contrast cystography is useful for identification of mucosal abnormalities and space occupying lesions

•excretory urogram is indicated to determine the location and extent of obstructive urinary tract disease when the urethra cannot be catheterized


Ultrasonography

•ultrasonography is recommended to determine the location and extent of bladder involvement, regional lymph node size and appearance, and involvement of adjacent anatomical structures such as the colon

•ultrasonography is superior to excretory urography and double-contrast cystography in detecting TCC




Transurethral Cystography

•transurethral cystoscopy is the principal method for the diagnosis of TCC in humans and has been used for the investigation of bladder diseases in cats and dogs

•transurethral cystoscopy provides a minimally-invasive method of assessing urethral mucosal surface and performing biopsies for staging and grading purposes




Biopsy

•biopsy is required for definitive diagnosis of urinary tract tumors

•biopsy techniques include FNA, needle biopsy, catheter biopsy, cystoscopic, and open surgery

•percutaneous biopsy procedures are not recommended due to the risk of tumor seeding

•catheter biopsy techniques correlate with surgical biopsy results in 73% of urethral and bladder tumors

•inflammation secondary to necrosis and ulceration is common and may result in false-negative findings


Tumor Markers

•bFGF is an angiogenic growth factor and a potential tumor marker for canine TCC but is not readily available

•bladder tumor antigen urine dipstick test measures a glycoprotein complex with a 85%-90% sensitivity for the detection of TCC in dogs

•35%-78% specificity with false-positive results common due to glucosuria (4+), proteinuria (4+), hematuria (> 30-40 red blood cells per high power field), and pyuria (> 30-40 white blood cells per high power field)

•bladder tumor antigen test sensitivity is improved by centrifuging urine samples prior to testing

•bladder tumor antigen test is a useful screening test to rule-out TCC, but does not provide a positive diagnosis



SURGICAL MANAGEMENT


General Considerations

•surgical techniques for management of bladder tumors include:

•palliative procedures: tube cystostomy ± partial cystectomy

•curative-intent procedures: partial cystectomy and total cystectomy with urinary diversion

•cystostomy tube can be placed percutaneously or with either laparoscopic or open surgery

•complications: stranguria, pollakiuria, hematuria, urine leakage around the stoma, and vesicoureteral reflux which predisposes to ascending UTI and tumor seeding of the upper urinary tract

•MST 86-142 days for partial cystectomy or surgical debulking alone, with 1-year survival rate up to 54.5%


Cystectomy and Urinary Diversion


General Considerations

•total cystectomy provides excellent control of local disease and is recommended in humans for invasive tumors, neoplastic involvement of the entire urothelium, or tumors located in the trigone or urethra

•urinary diversion techniques reported in veterinary surgery include:

•ureterocolonic or trigonal-colonic anastomosis

•ureterohysterostomy

•ureteroileostomy with perineal urinary diversion

•Koch pouch urinary diversion (or continent jejunal reservoir)

•bladder reconstruction using intestinal segments (i.e., iliocystoplasty)

•human techniques: Koch pouch urinary diversion and Indiana pouch continent urinary reservoir


Surgical Complications

•ureterocolostomy associated with poor prognosis in cats as 100% (5/5) died within 5 days due to surgical technique and ureteral obstruction from feces and peri-ureteral inflammation

•other complications include:

•UTI and pyelonephritis (30%-40%)

•neurologic disease associated with hyperammonemia (and nausea and vomiting)

•renal failure

•struvite urolithiasis

•hydronephrosis and megaureter secondary to ureteral obstruction and tumor recurrence

•ureterocolonic anastomosis in dogs also causes odorous and watery feces, intermittent vomiting, and pyelonephritis

•surgical complication rate is low in humans (7.5-9.0%)

•surgical complications reported in humans include:

•early: ileus, abscess, lymphocele formation, ureteral obstruction, and ilial anastomosis leakage

•late: ileus, abscess, neobladder-colon fistulation, ureteral obstruction, and hydronephrosis


Metabolic Complications

•use of intestinal segments for urinary bladder reconstruction or ureteral implantation results in the physiologic exchange of water and solutes between urine and blood due to the replacement of impermeable urothelial mucosa with permeable intestinal mucosa

•hyperchloremic acidosis and hyperammonemia are the most common complications:

•hyperchloremic acidosis is due to secretion of sodium and bicarbonate from GI and concurrent absorption of ammonium and chloride ions

•sodium chloride and water loss lead to dehydration

•chronic acidosis alters calcium metabolism and leads to osteopenia:

•acidosis enhances activity of osteoclasts which increases bone resorption

•acidosis inhibits 1α-hydroxylation of 25-hydroxyvitamin D in the kidney resulting in decreased absorption of calcium in the GI, hypocalcemia, and compensatory bone resorption

•hyperammonemia is associated with neurologic signs in affected dogs

•hypochloremic metabolic alkalosis occurs if gastric segments are used rather than intestinal segments

•other complications include vitamin B 12 deficiency, hyponatremia, hyperkalemia, and azotemia

•vitamin B 12 deficiency is occurs after 3-5 years in humans due to considerable body stores and manifests as megablastic anemia and demyelination of the lumbrosacral spinal cord

•malabsorption of bile salts results in secretory diarrhea, hyperoxaluria, and calcium oxalate urolithiasis


Prognosis

•poor prognosis for long-term survival with no dog surviving > 42 weeks

•survival is better when total cystectomy is performed for non-neoplastic disease:

•1 dog was reported to have survived almost 5 years following subtotal cystectomy and trigonal-colonic anastomosis for lymphocytic-plasmocytic urethritis

•1 dog with necrotic bladder survived > 1 year following modified cup-patch iliocystoplasty



ADJUNCTIVE MANAGEMENT


Chemotherapy

•intravesical and systemic chemotherapy have been investigated in the treatment of TCC

•TCC is divided into superficial and muscle-invasive disease based on the degree of bladder wall involvement

•intravesical chemotherapy is only indicated for superficial TCC which is rarely diagnosed in cats and dogs

•systemic chemotherapy is recommended due to the high risk of local and distant metastatic disease

•MST 181-195 days with piroxicam alone, including 3%-6% CR and 15%-20% PR

•piroxicam reduction in tumor volume significantly associated with induction of apoptosis and reduction in urine bFGF concentration

•MST 259 days with doxorubicin and cyclophosphamide

•MST 350 days with mitoxantrone and piroxicam, including 35% overall response rate with 2% CR and 33% PR

•MST 130-220 days with cisplatin alone, including 0% CR and 25% PR with MST significantly longer for responders (445 days v 70 days)

   •71% overall response rate when cisplatin is combined with piroxicam, but renal toxicity occurs in 87% dogs

•MST 132 days with carboplatin alone, but response rate is 0% and is not effective for the treatment of canine TCC

•32% overall response rate when carboplatin is combined with piroxicam, but response rate and MST 93 days not different to piroxicam alone

•MST 240 days with mitoxantrone and piroxicam combined with palliative external beam radiation therapy


Radiation Therapy

•external beam and brachytherapy used in dogs and humans with bladder tumors

•radiation therapy is associated with poor tumor control, distant metastases, and high complication rates

•extent of bladder irradiation required in dogs is much greater than the recommended maximum of 30% in humans as canine TCC often involves the entire bladder, urethra, and ureters

•MST 12-15 months following intraoperative radiation therapy of incompletely excised bladder TCC, with 12-month survival rate 61%, local tumor recurrence rate 46%, and metastatic rate 30%

•complications: ureteral stenosis, bladder wall fibrosis, urinary incontinence, cystitis, and stranguria



PROGNOSIS


Transitional Cell Carcinoma

•MST 86-142 days for partial cystectomy or surgical debulking alone, with 1-year survival rate up to 54.5%

•MST 181-365 days with surgery and various chemotherapy protocols

•combination of surgical debulking and chemotherapy significantly improves survival time (MST 272 days v 195 days for surgical biopsy only and 150 days for chemotherapy only)

•majority of canine TCC are associated with a poor prognosis due the advanced stage at diagnosis and proximity of the tumor to the trigone, ureters, and neurovascular supply of the urethra and bladder

•prognostic factors in dogs with TCC include:

•sex

•location and extent of the tumor

•clinical stage (i.e., local tumor invasiveness and metastatic disease)

•chemotherapy

•histologic grade

•spayed females survived significantly longer than castrated males (MST 358 days v 145 days)

•TCC of both the bladder and urethra or prostate have a worse prognosis than either the bladder or urethra alone and are associated with a higher clinical stage and pathologic grade

•dogs receiving platinum drug and either doxorubicin or mitoxantrone survived significantly longer than dogs receiving a platinum drug alone (MST 358 days v 132 days)















 

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T0

No evidence of neoplasia

Tis

Carcinoma in situ

Primary Tumor

T1

Superficial papillary tumor

T2

Tumor invading bladder wall

N0

No evidence of regional lymph node involvement

N1

Regional lymph node involvement (i.e., sublumbar lymph nodes)

Node

M0

No evidence of metastasis

M1

Evidence of distant metastasis with site specified

Metastasis

T3

Tumor invading adjacent organs (i.e., uterus, vagina, prostate, colon, etc.)

N2

Regional and juxta-regional lymph node involvement

Survival Rate

Distribution

0-1 month survival

1-6 month survival

Grade I

18%

39%

28%

Grade II

61%

60%

30%

Grade III

20%

85%

5%

7-12 month survival

> 12 month survival

22%

11%

5%

5%

5%

5%