Transitional Cell 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. 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.

Normal Urinary Tract

 

Urinary Tract with transitional cell carcinoma

Normal urinary tract showing kidneys, ureters, bladder, and urethra.
This is called a "half shell" view as if the tract were opened vertically for viewing.

 

Urinary tract with a transitional cell carcinoma growing in the bladder neck
and down the urethra.

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

transitional cell lining

Arrows indicate the transitional cell 
lining of the normal dog's bladder. 

Epithelial cells are cells that line areas of the body that interface with the outside environment. There are many different types of epithelial cells depending on the immediate environment they contact. The skin, for example, is a barrier against irritants and wounds. The tough cells that make up the skin are called “squamous” epithelial cells because of their flat overlapping, scale-like design which helps them form a barrier similar to the shingles of a roof-top. The epithelial cells of the respiratory tract secrete lubricant but also are designed to trap inhaled particles in secreted mucus and use tiny hair-like “cilia” to push them out of the lower tract and back upward where they can be coughed up. These are called “ciliated” columnar epithelial cells.

The urinary bladder is lined by “transitional cells.” They must protect the body from the caustic urine inside the bladder but also must maintain this barrier when the bladder stretches and distends with larger volumes of urine. A Transitional Cell Carcinoma is a tumor of the Transitional Cell lining of the urinary bladder.

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.

Shetland Sheepdog 200 wide

West Highland White Terrier 200 wide

Beagle 200 wide

Shetland Sheepdog

West Highland White Terrier

Beagle

Scottish Terrier 200 wide


Scottish Terrier

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. There are some circumstances under which further testing may be recommended.

Second Step: If no infection is found, if the urinalysis is normal despite obvious symptoms, or if a growth is palpable, radiographs would be the next step. The goal at this point would be to rule out a bladder stone. Bladder tumors are not visible on plain radiographs though sometimes some bony proliferations grow on the pelvic bones in reaction to bladder tumors.

Third Step: If no stone is visible on the radiographs, it may be a good idea at this point to do a bladder tumor antigen test (called a “V-BTA” test). This is an immunological test that detects antibodies generated in response to bladder tumor antigens. If the test is negative, there is a 90% chance that a bladder tumor is not present. If the test is positive, there is a reasonable possibility of a false positive so further testing is needed. In either case, further imaging is necessary so it is very reasonable to skip to the next step without doing this test. It has been suggested that large amounts of blood in the urine will interfere with the accuracy of this test. Since the usual symptoms suggesting the possibility of transitional cell carcinoma include bloody urine, it may be difficult to get a sample that is adequately "non-bloody." If interpretation of the test is likely to be confusing, it is often skipped.

Fourth Step: At this point, special imaging methods are needed to see inside the urinary bladder. This can be done with contrast radiography, ultrasound, or cystoscopy.

Contrast Radiography:

contrast radiography bladder

Radiograph of a bladder injected with radiographic dye. The top right of the bladder oval
is obscured, because of a “filling defect:” A transitional cell carcinoma is taking up
that space in the bladder, preventing the dye from “filling up” the entire space.

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.

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, a needle can be used to withdraw cells from it using ultrasound guidance to possibly make a positive diagnosis. Ultrasound is also necessary to determine the extent of tumor spread after diagnosis has been confirmed (see below). Ultrasound is not available in all hospitals and sometimes referral is necessary.

Cystoscopy: With cystoscopy a tiny camera on a flexible thin rod is inserted into the urethra and the bladder can be visualized. Small biopsy intruments can travel up the channel to collect tissue samples. This equipment is highly specialized and is not available even at referral facilities in many areas.

    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.

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 nodeshad 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 of 20 cats with TCC, the median survival time was 261 days.

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.

SURGICAL OPTIONS:

    Partial Removal of the Bladder

    If the tumor is fairly small at the time it is detected, 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.

    Permanent Urinary Catheter

    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

    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.

    Ureterocolonic Anastomosis

    With this procedure the entire urinary bladder is removed. 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. 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 (pets will need to urinate approximately every 4 hours).

    Laser Ablation with Chemotherapy

    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 solidfying these interpretations.

MEDICATION (CHEMOTHERAPY)

    Doxorubicin (same as Adriamycin)

    This intravenous medication in combination with cyclophosphamide (yes, the same cyclophosphamide that is known to cause bladder tumor development), provided a median survival time of 259 days in one study. Another study using doxorubicin in combination with cisplatin achieved a median survival time of 358 days. More studies are needed for more definitive response information. For details on this intravenous treatment, please click on the above link.

    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.

    Mitoxantrone

    A combination of piroxicam and mitoxantrone has been studied and yielded a measureable 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.

RADIATION THERAPY

    Special facilities are required to deliver radiation therapy so if one elects this sort of treatment some sort of travel is likely to be needed. Here, the patient is anesthetized, the bladder is surgically exposed and a radiation beam targets the tumor. In other techniques, the bladder is not surgically exposed and the radiation beam targets the tumor externally. It is not clear if one method produces better results. In most cases, surgery or chemotherapy is performed in conjunction with radiotherapy. Results have been variable with some very long survival times and some patients with short survival times. The urinary bladder tends to scar with exposure to radiation which leads to incontinence. More work is needed to develop a more clearly beneficial radiation therapy protocol for the treatment of bladder tumors.

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:

www.perseusfoundation.org/new-petowner/onc_locate.cfm

Cancer treatment for a pet can be an expensive and emotionally exhausting.Animal Clinical Investigation LLC logo Sometimes participation in a study where treatment is free is helpful.

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: 9/1/2013