TRANSITIONAL CELL CARCINOMA
(ALSO CALLED UROTHELIAL CARCINOMA)

The transitional cell carcinoma (frequently abbreviated "TCC") is a particularly unpleasant tumor of the urinary bladder. In dogs, it usually arises in the lower neck of the bladder, where it is virtually impossible to surgically remove, and causes a partial or complete obstruction to urination. The urethra (which carries urine outside the body) is affected in over half the patients diagnosed with transitional cell carcinoma; the prostate gland of male animals may also be involved and the tumor can spread to distant sites (other body areas) in approximately 50% of cases. In cats, the site of the tumor within the bladder is more variable. Bloody urine and straining to urinate are typically the signs noted by the owner, whether the patient is a dog or a cat. These signs are, of course, exactly what would be expected in event of a bladder infection (frequently present concurrent with the tumor) making diagnosis somewhat challenging.

WHY IS THIS TUMOR CALLED A “TRANSITIONAL CELL” CARCINOMA?  IS SOMETHING IN TRANSITION? 

While bladder tumors are somewhat rare as types of cancers go in pets,
more than half (and possibly up to 70%) of the bladder tumors
developed by pets are transitional cell carcinomas.

WHAT CAUSES THIS TUMOR?

As with most cancers, we do not know many specific causes. Presumably, repeated exposure to carcinogens in the urine is an important cause. We know that chemotherapy with cyclophosphamide is a cause. We know that female dogs tend to get more transitional cell carcinomas than male dogs (possibly because females do less urine marking and are thus possibly storing urinary toxins longer). In cats, however, males have an increased risk over females. Urban dwelling and obesity have been found to increase the risk for the development of this tumor. We know that Shetland sheepdogs, West Highland White terriers, Beagles, and Scottish terriers seem to be predisposed breeds. Beyond this, specifics remain unknown.

Scottish Terrier (Photocredit: Mider via Wikimedia Commons)

A recent study showed that exposure to phenoxy herbicide treated lawns increased the risk of developing TCC in the Scottish terrier. Another study investigating TCC in Scottish terriers found that the risk for development of this tumor could be reduced by feeding yellow/orange or green-leafy vegetables at least three times per week.

The average age at diagnosis in the dog is 11 years.
The median age at diagnosis in the cat is 15 years.

WHAT KIND OF TESTING IS NEEDED TO IDENTIFY THIS TUMOR?

Bloody urine with straining can be caused by many other conditions besides cancer. A severe bladder infection, a bladder stone, or Feline Lower Urinary Tract Disease would be far more common and must be explored first. In other words, reaching a diagnosis is a step-by-step procedure whereby the most common conditions are ruled out one by one until a diagnosis is confirmed.

First step: Urinalysis and culture. Many people are confused by the difference between these two tests. A urinalysis is an analysis of urine including the a brief chemical analysis and a microscopic examination of the cells contained in the sample. A culture involves plating a sample of urine sediment on growth medium, incubating for bacterial growth, identifying any bacteria grown, and determining the what antibiotics are going to be effective. Urinalysis and culture will rule in the presence of a bladder infection. (The presence of documented infection absolutely does not rule out the presence of a tumor as tumors may easily become infected). About 30% of transitional cell carcinomas will shed tumor cells into the urine which may be identified as such on the urinalysis. If an infection is identified in the bladder, it may be worthwhile to simply treat it with the appropriate antibiotic and see if the clinical signs resolve. If signs do not resolve or if they promptly recur, further testing is definitely in order.

A urine dipstick measuring different chemical properties of the urine sample is part of the urinalysis. (Photocredit: Grook da Oger via Wikimedia Commons)

Second Step: If not infection is found, if the urinalysis is normal despite obvious symptoms, if symptoms do not resolve with treatment for infection or if there is some other reason to be suspicious of a continuing problem, imaging (usually radiographs or ultrasound) would be the next step. The presence of a bladder stone would be a vastly more common scenario than a tumor but it may not be possible to rule out both of these with one test. Radiography is generally less costly and more available than ultrasound, but ultrasound offers the ability to view soft tissue structures inside the bladder, which radiography cannot. This means that tumors are not visible to radiographs (though most stones are) while both stones and tumors are generally visible to ultrasound.

Ultrasound: Ultrasound uses sound waves to create an image of structures within the urinary bladder. This presents a non-invasive way to detect radiolucent stones, polyps, or tumors within the bladder. If a growth is found, it is tempting to sample the cells by needle aspirate; however, the TCC is famous for seeding other organs via needle track so it best not to attempt aspiration. Sampling is best done by cystoscopy. Ultrasound is helpful in determining the extent of tumor spread after diagnosis has been confirmed (see below). Ultrasound is not available in all hospitals and sometimes referral is necessary.

Ultrasound image of a Transitional Cell Carcinoma in a dog's bladder neck.
(Photocredit: DVMSound)

Radiography: The main use of radiography at this point is to rule out obvious bladder stones as they are a common cause of bloody urine and urinary straining. The presence of stones in the bladder provides an explanation for the symptoms and the focus can be shifted to management of stones (removing the stones present and preventing new ones from developing). Because radiography cannot distinguish urine from bladder tissue, plain radiographs cannot show tumors without special contrast agents but, again, if stones are found then there is usually no reason to look further. Finding a mass in the neck of the bladder is often all that is needed to diagnose transitional cell carcinoma.

A New Test for Dogs: the BRAF Mutation Test
A non-invasive test for transitional cell carcinoma has been validated for dogs. It turns out that 85% of canine transitional cell carcinomas have a mutation called the BRAF mutation and this mutation can be detected in a urine sample well before the tumor is visible via the special imaging as described below. The BRAF test can be used to screen apparently normal dogs who are members of "at-risk" breeds or it can be used to investigate a dog with symptoms when there is a question of tumor presence. The test is not available for cats and it requires 30cc of urine (a relatively large sample). It also should be remembered that 15% of dogs with transitional cell carcinomas do not express the BRAF mutation and will test negative. This test is completely different from the BLAT (bladder tumor antigen test) which was not very helpful as it was not accurate in the presence of a bloody urine.

Third Step: If an explanation for the patient's symptoms has still not been determined, at this point, specific imaging methods are needed to see inside the urinary bladder. This can be done with contrast radiography, where special dye is injected into the bladder to outline any solid material inside the bladder. For a more detailed exploration, cystoscopy can be employed where a tiny camera is threaded through the urinary tract to view and possibly even biopsy the bladder wall.

Contrast Radiography:

With this technique, a combination of radiographic dye and air are injected into the bladder via a urinary catheter. This allows definition of structures within the bladder such as bladder stones which are “radiolucent” (i.e., do not show up on plain radiographs), polyps (benign growths in the bladder caused by chronic inflammation) or tumors. The procedure is simple and probably the least expensive of all three methods as most animal hospitals have the equipment to perform contrast radiography. The problem is that female animals are rather difficult to catheterize. If the patient is a female, ultrasound may be a better choice.

The finding of a mass in the neck of the bladder
even with inconclusive tissue samples
is often all that is needed to make the diagnosis
of Transitional Cell Carcinoma.

Other Techniques: A tissue sample, of course, is ideal for confirming the diagnosis and cystoscopy generally requires referral. Sometimes a urinary catheter can be placed and manipulated in such a way as to harvest cells through the tumor. A rectal examination sometimes reveals swelling in the area of the urethra which would be highly suspicious of a transitional cell carcinoma in a patient with consistent symptoms.

TRANSITIONAL CELL CARCINOMA HAS BEEN DIAGNOSED. NOW WHAT?

When your pet is diagnosed with cancer most people want to know how long their pet has to live and what treatments are available. Prognosis depends on the stage of the disease (i.e. whether the tumor is invading other local organs, whether there is evidence of lymph node spread, if there is evidence of distant tumor spread.)

In one study, median survival time was 118 days for dogs with evidence of tumor invasion of other local organs compared with 218 days for dogs with no evidence of invasion beyond the urinary bladder.

Dogs with no involvement of local lymph nodes had a 234 day survival time compared to 70 days for dogs with local lymph node involvement.

Dogs with evidence of distant tumor spread had a median survival time of 105 days while those without distant spread had a survival time of 203 days.

In one study (Wilson et al, Journal of the AVMA; July 2007) involving of 20 cats with TCC, the median survival time was 261 days (this statistic includes cats with various treatments including no treatment).

Ultrasound of the belly is needed to assess the involvement of local lymph nodes and whether or not other organs have been invaded. Radiographs of the chest are the usual way to screen for distant tumor spread; most tumors will spread to the lung leaving visible round opacities there.

WHAT ARE THE TREATMENT OPTIONS?

Any way you look at it, this transitional cell carcinoma is bad news. It is aggressively malignant and generally grows in an area not very amenable to surgical removal. If the tumor becomes so large and deeply invasive that the patient cannot urinate, an unpleasant death ensues in a matter of days. Ideally, the tumor is discovered and addressed before it gets to this point. There are two approaches that can be explored: "definitive" treatment (basically treating aggressively with the intent achieve a long remission or even cure) and "palliative" treatment (treating so as to restore temporary comfort only).

SURGICAL OPTIONS:

Partial Removal of the Bladder (palliative treatment)

If the tumor is fairly small at the time it is detected (there is room enough for margins of 3 cm of normal bladder to be removed around the tumor), it may be worth attempting to remove it and this means removing part of the bladder. If one is very lucky, complete removal or very long term survival is possible. (In one study over half the patients were alive a year after surgery!) Problems with this therapy include: the fact that it is not possible to determine with the naked eye what the margins of the tumor actually are (so it is easy for the surgeon to believe they have removed enough tissue when in fact there is more tumor present), and reduced storage capacity of the remaining bladder after surgery leads to need to urinate more frequently. If recurrence happens it generally does so within one year of surgery and is thought to occur from either inadequate tumor removal during surgery or development of a new tumor via the same mechanism that led to the development of the original tumor. There is evidence that using a cyclooxygenase inhibiting anti-inflammatory medications (deracoxib, ) have activity against the TCC and can assist in prevention of recurrence; still, 80% of tumors will eventually recur.

Complete Removal of the Bladder (definitive treatment)

Complete removal of the urinary bladder is just as invasive as it sounds. The benefits of this drastic procedure include long term control of the tumor even if the tumor is large (median survival times are greater than 6 months in patients not receiving any other treatment) and control of the pain associated with the tumor.

The main problem with this surgery is the resultant incontinence. The kidneys (where urine is produced) normally deliver urine to the bladder for storage via tiny tubes called ureters. After the bladder is removed, the ureters are attached to the colon so that the patient effectively passes urine rectally along with stool. Alternatively, the ureters can be attached to the vagina or another area.

This is a very radical surgery and potential complications can include scarring of the ureters and loss of kidney function, infection, and blood biochemical abnormalities. Special diets are required after surgery as well as long term antibiotics, frequent blood test monitoring, and free access to an area for urination or pet diapers will be needed.

Permanent Urinary Catheter (palliative treatment)

A permanently placed urinary catheter can be implanted in the patient’s urinary tract to create more comfortable urination. The placement of a foreign body in this way will predispose the patient to bladder infection and frequent screening cultures will be needed; still, in one study six out of seven owners reported satisfaction with results in their pets. Obviously, this procedure does nothing to actually hinder the growth of the tumor. Owners will need to empty the bladder with a drainage tube at least 3 times a day to avoid stagnation of urine. The entrance to the catheter must be kept clean and must be cleaned daily. Tube dislodgement is a serious complication. Newer tubes are made to be very short and a longer drainage tube is attached during bladder emptying. More traditional permanent catheters are longer and will require some sort of wrap or garment for protection. If a tube dislodges, it must be replaced by within 48 hours as scar tissue rapidly forms to close the opening into the bladder. Sedation is required for tube replacement; it is not something an owner can do at home.

Urethral Stenting (palliative treatment)

In this procedure, a metal stent is placed in the urethra to allow the passage of urine through the tumor. This is a similar concept as the permanent catheter but more "high tech." The stent is placed either surgically or with a special video radiography called "fluoroscopy." The procedure is relatively simple and not invasive but does require special equipment. Urinary incontinence is unfortunately a common problem after this procedure and special garments/diapers may be needed indoors.

Laser Ablation with Chemotherapy (palliative treatment)

A study was published in the February 15th, 2006 issue of the Journal of the AVMA where 7 dogs with transitional cell carcinomas were treated with a combination of laser ablation, piroxicam (see below) and mitoxantrone (see below). Laser ablation is a treatment that has been used for many years in humans with urinary tract cancer. In short, a surgical laser is used to vaporize the tumor from the surface of the bladder and urethra. In the study above, the 8 dogs received this treatment followed by chemotherapy and their symptoms and survival were tracked. Median disease-free interval (i.e. the time without significant symptoms) was 200 days and median survival time was 299 days. These survival times were felt to be similar to those achieved with chemotherapy alone and no surgery at all; however, a more lasting resolution of symptoms was felt to have been achieved with this combination treatment. Please note, only 7 dogs were studied (an 8th received treatment but died after the first chemotherapy treatment from an automobile accident); information from a larger population would be helpful in solidifying these interpretations. This form of treatment is not without controversy at this time.

MEDICATION (CHEMOTHERAPY)

There are numerous protocols involving different combinations of cyclooxygenase inhibitors (Non-steroidal Anti-inflammatory drugs) and chemotherapy agents. It has been recommended that the tumor be re-staged every 6-8 weeks to determine if a revision in therapy is needed and, of course, complete staging should be done at the beginning to select the most appropriate treatment. If the tumor is found to be the same size or smaller when it is re-staged, then the protocol is deemed to be working and should be continued so long as there are no problems with unacceptable medication side effects.

PIROXICAM

This medication is a non-steroidal anti-inflammatory drug, previously used in the treatment of canine arthritis but largely abandoned for this use with the development of safer products. It is not clear if this medication works because of its anti-inflammatory effect or if it actually has anti-tumor effects, both therapeutically and preventively. This medication is inexpensive, given once a day (or less in the cat), available through most human pharmacies, and administered orally. Because of these qualities, it has become especially popular as a conservative therapy. Side effects include potential for stomach ulcers and effects on the kidney though these can be addressed with additional medications should they become problematic. In the 2003 study by Knapp, 62 dogs with TCC were treated with piroxicam alone. The median survival time was 195 days with 3% of dogs experiencing complete remission, 14% with partial remission, and 56% with no change in tumor size. These results are impressive considering no conventional chemotherapy was involved.

Since COX-2 selective anti-inflammatory drugs have dominated canine pain control for the last two decades, there has been interest in whether these safer NSAIDs have similar activity against the TCC. Research with deracoxib suggests that they do. Many specialists prefer to recommend piroxicam as most research has been conducted with this specific medication but as new research emerges, this may change.

Mitoxantrone

A combination of piroxicam and mitoxantrone has been studied and yielded a measurable response in 35% of patients. Approximately 18% had intestinal side effects and 10% had kidney related side effects. The median survival time was 350 days. For many oncologists, this protocol is the first choice in therapy. Daily oral piroxicam is used and intravenous mitoxantrone is given every 3 weeks for four treatments.

OTHER CHEMOTHERAPY

Lately research with cisplatin and its more kidney-friendly relative carboplatin has shown some success with remission rates up to 70% when used in combination with piroxicam. Newer work with intravenous vinblastine is promising but there have been bone marrow suppression issues in some patients.

RADIATION THERAPY

In the past, radiotherapy for bladder tumors has been problematic because of the proximity of the large intestine. In other words, it has been hard to irradiate the bladder tumor without also irradiating the large intestine and causing scarring or other radiation injury. Newer technology has allowed for 3D imaging with CT Scans so as to provide for "Intensity Modulated Radiotherapy." This has allowed for better targeting of the tumor. (A study of 21 dogs revealed a median survival of 654 days.) Special facilities are required to deliver radiation therapy and this special new technology may not be readily available so if one elects this sort of treatment some sort of travel is likely to be needed.

Additional Links

For more detail on specific treatments, we recommend a consultation with an oncology specialist. To find an oncologist in your area, either ask your veterinarian to arrange a referral or use this link:

http://vetcancersociety.org/pet-owners/find-a-vcs-member  

Animal Clinical Investigation LLC is a Maryland based Limited Liability Company founded by Chand Khanna, DVM, PhD, Diplomate - American College Veterinary Medicine (Oncology). The mission of Animal Clinical Investigation LLC is to help in the development of new treatment opportunities for pet animals with cancer through the design and implementation of prospective clinical trials.

To review on-going studies and learn how to qualify for free treatment, visit:

www.animalci.com

 Page last updated: 9/24/2020