Update on transitional cell carcinoma (Proceedings)

Incidence

Bladder tumors represent < 2% of all canine malignancies. Transitional cell carcinoma is the most common histologic type diagnosed in both cats and dogs. The trigone is the most common site for primary tumors in dogs.  The prevalence of bladder tumors has continued to increase over the past 25 years with increased environmental toxin exposure and better prevention medicine. The majority of these tumors are high grade, we rarely find low grade tumors in the dog.

Signalment

The mean age of affected dogs is 11 years old with a mean body weight is 15.7 kg (+/- 10 kg). The most common presenting signs most commonly include:

·         Hematuria

·         Stranguria

·         Dysuria

·         Lethargy

·         Occasionally- lameness and weight loss

Risk factors in dogs

This disease has a multifocal etiology including exposure to all of the following:

·         Topical insecticides

·         Proximity to marshes sprayed for mosquitoes

·         Obesity

·         Female gender (1.7:1)

·         Overall industrial activity of host county

·         Breed predilection:

o    Scottish Terriers, West Highland White Terriers, Shetland Sheepdogs, Beagles, Wire Haired Fox Terriers

·         Neutered animals

·         +/- previous Cyclophosphamide therapy

Risk factors in humans

Similar risk factors have been identified in humans as well.  All of the following are associated with the development of TCC in humans:

·         Caucasians

·         Men > Women

·         Smoking (the risk increases with number of cigarettes smoked per day)

·         House hold chemical exposure

Herbicide exposure

A study retrospectively compared herbicidal exposure in Scottish Terriers to Scottish Terriers without herbicide exposure.  Comparisons were made from histories of dogs with and without TCC as well.  A significantly higher risk of TCC in Scottish Terriers exposed regularly to insecticides (4.4 times more likely) was noted compared to those not exposed at all. The most common herbicide exposure was to phenoxy herbicides (2,4-D in particular).  There is controversy as to whether these chemicals or the inactive ingredients are the true carcinogens.

Diagnostics

The following diagnostics may be useful for the identification and definitive diagnosis of bladder tumors in dogs.

·         Abdominal radiographs

·         Abdominal ultrasound

o    Best if the bladder is distended with urine or saline

o    Helpful for determining intra-abdominal metastasis

o    Ultrasound guided traumatic catheterizations

·         Double contrast cystourethrogram

o    Positive identification of bladder mass 95% of the time

·         Traumatic catheterization- Recommended diagnostic test if possible

·         Surgical biopsy- if cannot get a pre-operative sample safely any other way

·         Fine needle aspirates

o    Risks of implantation of tumor cells

o    Reported in dogs and cats

o    Smaller gauge needles reportedly have less risk associated with them than larger gauge needles

o    May need to remove aspiration site if surgery is performed to remove the bladder mass- can mark it with a suture or a permanent marker!

o    Surgical biopsies can also lead to seeding of surgical site- so keep your instruments clean and switch them out after handling the tumor cells!

Other diagnostics

Other diagnostics have been described to help with the diagnosis of bladder tumors in dogs.  The veterinary bladder tumor antigen test is a rapid latex agglutination test that uses an antibody to a bladder tumor associated glycoprotein complex detectable in urine. This test requires 0.5 ml of urine that should be centrifuged before testing. The test should be run within 48 hours of the sample collection.

The accuracy of the VBTA test is questionable at best.  A study was performed to determine how effective the test was.  229 canine urine samples were tested. Forty-eight samples were suspected (3) or confirmed (45)TCCs. The rest were divided into healthy dogs and dogs with non TCC urinary disease. The sensitivity for TCC cases was 88% and the sensitivity for healthy cases 84%.  However, the sensitivity for non TCC urinary disease was only 41%. A negative test correlated with the absence of TCC but a positive test warrants further investigation.

Staging

A good physical exam including a rectal exam is paramount for the diagnosis and staging of TCC. Other important tests include a minimum database: CBC, biochemistry panel, urinalysis, thoracic radiographs and imaging of bladder and abdomen via abdominal ultrasound or a CT scan (used if there any concerns that cannot be answered by US).

                                                World Health Organization Staging for Transitional Cell Carcinomas

T: Primary Tumor Tis Carcinoma in situ T0 No evidence of primary tumor T1 Superficial papillary tumor T2 Tumor invading the bladder wall, with induration T3  Tumor invading the neighboring organs (prostate, uterus, vagina, and pelvic canal)

  N: Regional Lymph node (internal and external iliac lymph nodes) N0 No regional lymph node involvement N1 Regional lymph node involved N3 Regional lymph node and juxt-regional lymph node involved

M: Distant metastasis M0 No evidence of distant metastasis M1 Distant metastasis present

Metastases

TCC tends to spread late in the disease process; however, we tend to diagnosis this disease late in the disease process as well. Metastatic rates at the time of necropsy have been reported to be as high as 40-50%.  Distant metastasis at the time of diagnosis is a negative prognostic factor. Reported sites of metastasis include the lungs 28%, regional lymph nodes 26%, distant nodes 4%, liver 18%, kidneys 4%, spleen 4%, bone 4% and uterus 4%.

Lung Metastasis can present as several different patterns including an unstructured interstitial opacity that can be mistaken for age related changes with a “lace-like semidense diffuse opacity”. This pattern was misdiagnosed in 3 of 8 dogs with pulmonary metastasis in one report.

Treatment options

Surgery may be difficult because of location of tumor in dogs.  Up to 20% of dogs will have metastasis at the time of diagnosis as well making surgery less rewarding. A complete cystectomy is generally considered unreasonable to attempt in dogs. Partial cystectomies can be attempted and are the best options if possible. Margins should be taken as generously as possible but recurrence is still seen in 8/10 cases. Post-operative complications include pollakiuria, dehiscence of bladder surgery site and seeding of surgical site. Prepubic cystotomy catheters and indwelling cystotomy tubes may be used to palliate to alleviate obstructions.  This procedure leads to an increased risk of bacterial or fungal bladder infections.

Ureterocolonic anastomoses have a high complication rate for pylonephritis, stricture, and sepsis. After this procedure, dogs require a low salt, low protein diet with bicarbonate supplementation. These pets require frequent access to outside (~ every 4 hours) to prevent in house accidents. Vaginourethroplasty and ileocystoplasty have been reported in humans but are not feasible in the dog due to anatomy.

Surgical debulking decreases the tumor burden in an attempt to make adjunctive therapies more successful and may help to decrease symptoms associated with the tumor.  This is controversial; however, and many people feel that the potential complications outweigh any benefits gained by this procedure.

 Bladder reconstruction entails performing a complete cystectomy with the use of a small intestinal submucosal graft using a biodegradable collagen based material derived from pig intestines.  Many complications including failure of the graft may occur.  This procedure is not widely used in veterinary medicine.

Chemotherapy

Combination chemotherapy is most likely the best way to treat these tumors. Bladder epithelium is designed to pump out toxins and chemotherapy alone may not be very effective for very long. Piroxicam is typically added to one of the following chemotherapy drugs:

Doxorubicin

·         General Info: Derived from Streptomyces. Causes intercalation of DNA (inhibits protein synthesis), iron dependant oxygen free radical formation and inhibits topoisomerase enzymes. Cell cycle nonspecific.

·         Doses: 30 mg/m2 IV q 3 weeks (1 mg/kg or 25 mg/m2 can be used in dogs <15 kg), should be given slowly 0.5 ml/min

·         Toxicity: Severe vesicant! Allergic reactions while administering.  More likely to cause GI side effects, myelosuppression and alopecia than other drugs. Cardiotoxic- maximum recommended cumulative dose is 180-240 mg/m2

Mitoxantrone

·         General Info: Synthetic, inhibits topoisomerase II, no free radical formation, not cell cycle specific

·         Dose: 5.5 mg/m2 in dogs and 6.5 mg/m2 in cats, should be diluted up to 50ml with 0.9% NaCl or D5W

·         Toxicity: $$$$, moderately toxic- Myelosuppression most common, GI side effects, urine and sclera may turn blue or green

Cisplatin

·         General Info: Heavy metal compound that binds between DNA strands and prevents protein synthesis.  Cell cycle nonspecific.  Binds rapidly to plasma proteins and renally excreted.

·         Dose: 50-70 mg/m2 IV q 3 weeks with saline diuresis and antiemetic therapy

·         Toxicity: Immediately emetogenic within 1 hour of administration, nephrotoxic (always requires diuresis with 0.9% NaCl at 18.3 ml/kg/hr for 6 hours.) 

·         Discontinue piroxicam 48 hours before and 48 hours after administering this drug

·         Cisplatin splats cats!!! Fatal pulmonary edema!!!

Carboplatin

·         General Info: Binds within DNA strands and inhibits protein synthesis, platinum containing compound, cell cycle nonspecific, excreted via the kidneys

·         Dose: 300 mg/m2 IV over 5-10 min. q 3 weeks (dogs), cats 240-260 mg/m2 IV q3-4 weeks

·         Toxcity:  Moderate to severe myelosuppression with a double nadir around 7-10 days and 21 days.  Some cats require 4 week dose intervals because of second nadir.  Can also cause GI toxicity. 

Nonsteroidal Anti-inflammatory drugs (Piroxicam)

·         General Info: Nonsteroidal anti-inflammatory drug, COX1 and COX2, anti-tumor effects are inhibition of prostagladins, antiangiogenesis, decreases tumor's ability to protect itself from the immune system

·         Dose: 0.3 mg/kg daily- not stable as a liquid

·         Toxicity: Hepatic, renal papillary necrosis, GI ulceration- generally associated with COX 1 inhibition. Should not be given with other nephrotoxic drugs

Radiation therapy may be combined with chemotherapy.  We are finding better ways to deliver radiation therapy to dogs with bladder tumors to limit the side effects. Intraoperative radiation therapy consists of delivery of a single large dose of radiation to the tumor intraoperatively. Side effects of this treatment can be severe.  Ureters may stenose and become fibrotic when irradiated, the bladder often becomes fibrotic and loses distensability within 1-2 months and this may lead to incontinence. Chronic cystitis may also be a sequela of large single dose radiation therapy.

External beam radiation therapy has similar side effects to intraoperative radiation when definitive protocols are used.  Chronic colitis may develop secondary to radiation side effects and gastrointestinal perforation is possible with delivery of radiation to the small intestines.

Palliative therapy may have fewer side effects than definitive therapy and more and more reports are showing that this may be safe and effective for dogs with bladder tumors.  Palliative therapy delivers 4 doses of radiation once a week rather than daily radiation therapy.

Photodynamic therapy typically uses chemicals such as 5 Aminolevulinic acid (ALA) induced Protoporphyrin IX to cause DNA damage and kill cells.  ALA is generally well tolerated when given orally.  The fluorescence has been confirmed in the bladder mucosa but does not appear in the muscularis or serosa.  Therefore, this technique is only good for in situ or early lesions which is why it is rarely helpful in veterinary medicine.

Prognosis

Average median survival times have been reported as 4-9 months regardless of the treatment instituted. Several factors may limit the response to therapy:

·         Anatomic location of the tumor preventing surgical excision or debulking.

·         Limited efficacy of chemotherapy.

·         The degree of invasion into the bladder wall is prognostic

Favorable prognostic factors:

·         Minimal invasion of tumor into bladder wall

·         A tumor that is amendable to surgical excision

·         No involvement of the urethra or prostate

·         No involvement of regional lymph nodes

·         No distant metastasis

A brief note about cats

The signalment of cats is not as well described as in dogs. The most commonly affected breed reported for cats is domestic short haired cats, however the disease has been reported in Siamese, Abbyssinian and Somali cats.  In cats there is a male predilection (66.6%) when compared to females (33.3%). Most animals in the literature are neutered, though given the hospital populations of cats seeen, we are not sure if this is a risk factor. The median age at diagnosis is around 15 years of age.

Clinical signs in cats are similar to those seen in dogs and include:

·         Hematuria

·         Stranguria

·         Pollakiuria

·         Obstruction

·         Inappropriate Urination

·         No Signs have been reported and mass have been found incidentally.

Location           

The majority of masses in cats (57%) occur in the bladder wall with less than half (43%) occurring in the trigone.  Cats are also less likely to have urethral involvement.

Prognosis

Overall median survival for all cats diagnosed with bladder tumors is poor (~100 days).

Surgery plus chemotherapy may be the best treatment option if possible but further research needs to be done.