What Is Transitional Cell Carcinoma (TCC)?

The most common type of bladder cancer is called transitional cell carcinoma (TCC). Also known as urothelial carcinoma (UCC), TCC arises from the inner lining of the urinary tract, called the transitional urothelium.

This article looks at transitional cell carcinoma, its signs and symptoms, and its causes and risk factors. It also discusses diagnosis, staging, treatment, and prevention.

Signs and Symptoms

Symptoms of TCC will vary by the location of the tumor. TCC can develop in tissue from anywhere along the urinary tract, including:

• The renal sinus (the cavity within the kidneys)
• The ureter (the tubes connecting the kidneys to the bladder)
• The innermost lining of the bladder
• The urethra (the tube from which urine is expelled from the body)
• The urachus (the remnant of the fetal channel between the bladder and naval)

TCC is a slow-developing cancer with a latency period of anywhere up to 14.5 years. The latency period is the amount of time that passes between your exposure to a toxin or disease-causing agent and the development of symptoms.

In the earlier precancer stage, symptoms can often be vague to nonexistent. It is typically only when the cancer is advanced that many of the symptoms appear.

When symptoms do appear, they may resemble the symptoms of a severe kidney infection. You may have painful urination and lower back or kidney pain. The symptoms can also mimic those of other conditions, including:

• Cystitis
• Prostate infection
• Overactive bladder

For these reasons, TCC is usually diagnosed in older people. Around 60% of new diagnoses and 70% of deaths are in people over 65.

Depending on the stage of the disease, the symptoms of TCC may include:

• Visible blood in the urine (gross hematuria)
• Painful or difficult urination (dysuria)
• Frequent urination
• A strong urge to urinate but an inability to do so
• Flank pain to one side of the back just below the ribs
• Fatigue
• Weight loss
• Loss of appetite
• High fever with profuse sweating
• Swollen lower extremities (edema), usually in later-stage disease

Causes and Risk Factors

Cancer of the bladder or kidneys is often related to cigarette smoke. In fact, around 50% of TCC diagnoses in males and 30% in females are associated with smoking. Moreover, the risk and stage of the disease appear directly linked to the number of years a person has smoked and the daily frequency of smoking.

Research also suggests that bladder cancer in smokers is not only more prevalent but usually more invasive than it is in nonsmokers. The cause for this association is not entirely clear, but some have hypothesized that long-term exposure to tobacco smoke causes chromosomal changes in in the tissues that give rise to lesions and cancers. The risk is seen to be highest in persons who smoke 15 or more cigarettes a day.

Other risk factors for TCC include:

• Older age, with around 90 percent of new diagnoses in people 55 or older
• Being male, due largely to active androgen (male sex hormone) receptors, which play a key role in the development of TCC
• Being white, which places you at double the risk compared to African Americans and Latinos
• Family genetics, particularly involving mutations linked to Cowden disease (PTEN gene), Lynch syndrome (HPNCC gene), or retinoblastoma (RB1 gene)
• Obesity, which increases your risk by approximately 10%
• Workplace exposure to aromatic amines used in the dye and printing industries as well as in the manufacture of rubber, paint, and petroleum products
• Prior use of the chemotherapy drug Cytoxan (cyclophosphamide)
• Use of the diabetic medication Actos (pioglitazone) for more than a year
• Use of herbal supplements containing aristolochic acid, also known as Pin Yin in traditional Chinese medicine

Diagnosis

The first sign of TCC is often blood in the urine. Sometimes the blood is not visible, but it can be easily detected in a urinalysis (urine test). A urine cytology test can also be used to look for cancer cells in urine. This is a less reliable form of diagnosis, however.

Newer technologies can identify proteins and other substances in urine associated with TCC. These include the Urovysion and Immunocyt tests. There is even a prescription home test known as Bladderchek. This test can detect a protein called NMP22 commonly found at higher levels in people with bladder cancer.

The current gold standard for diagnosis is a biopsy obtained during a cystoscopy. The cystoscope is a long flexible tube equipped with a micro-camera. During this test, it is inserted into the urethra to view the bladder. A biopsy involves taking a sample of suspicious tissue for examination by a pathologist.

Depending on the type of cystoscope used, the procedure may be performed under local or general anesthesia. General anesthesia may be used for males since the male urethra is longer and narrower than in females, and the procedure can be extremely painful.

Cancer Staging

If a cancer diagnosis is made, the oncologist will classify it by stage. This is done using the TNM staging system. The TNM system describes the size of the original tumor ("T"), the infiltration of cancer into nearby lymph nodes ("N"), and the extent of metastasis ("M"). Metastasis is when cancer spreads to distant parts of the body.

The goal is to neither undertreat or overtreat the cancer. Based on these findings, your healthcare provider will stage the disease as follows:

• Stage 0 is when there is evidence of precancer but with no lymph node involvement or metastasis.
• Stage I is defined by the spread of cancer from the lining of the bladder to the connective tissue just below but with no lymph node involvement or metastasis.
• Stage II is when the cancer has spread even further to the muscle layer below but has not passed through the organ wall. Still, no lymph node involvement or metastasis is detected.
• Stage III is when the cancer has grown beyond the organ wall but has not spread to nearby lymph nodes.
• Stage IV is when the cancer has either spread to distant organs, nearby lymph nodes, or both.

The staging also provides a better sense of survival times. These numbers are not set in stone, and some people with advanced cancer can achieve complete remission irrespective of the diagnosis.

Earlier diagnosis, however, is almost always associated with better outcomes. The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program database tracks five-year relative survival rates based on how much the cancer has spread at diagnosis. The SEER database, however, does not group cancers by TNM stages (stage I, stage II, stage III, etc.). Instead, it groups bladder cancers into localized, regional, and distant stages:

• Localized: There is no sign that the cancer has spread outside of the bladder. For people who have abnormal cells that have not spread from their original location, the five-year survival rate is approximately 90%. For localized disease it is approximately 70%.
• Regional: The cancer has spread from the bladder to nearby structures or lymph nodes. The five-year survival rate is approximatively 36%.
• Distant: The cancer has spread to distant parts of the body such as the lungs, liver or bones. The five-year survival rate is approximatively 5%.

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Treatment Approaches

Treatment of TCC is largely dependent on the stage of the disease, the extent to which the cancer has spread, and the type of organs involved. Some of the treatments are relatively simple with high cure rates. Others are more extensive and may require both primary and adjunctive (secondary) therapies.

Stage 0 and I Tumors

Tumors that have not yet reached the muscle layer can often be “shaved off” in a procedure called a transurethral resection of bladder tumor (TURBT). This is done with an electrocautery device attached to the end of a cystoscope. The procedure may be followed with a short course of chemotherapy. In two out of three cases, immunotherapy treatments using a vaccine known as Bacillus Calmette-Guérin (BCG) can also lessen the risk of recurrence.

Stage II and III Cancers

These are more difficult to treat. They require extensive removal of any affected tissue. In the case of the bladder, these cancers may be treated with a surgical procedure known as radical cystectomy, in which the entire bladder is removed. A partial cystectomy may be performed in a small handful of stage II cases but never stage III.

Chemotherapy may be given either before or after surgery, depending largely on the size of the tumor. Radiation may also be used as an adjuvant therapy but is almost never used on its own.

Stage IV Cancers

Stage IV cancers are very hard to get rid of. Chemotherapy with or without radiation is typically the first-line treatment with the aim of shrinking the size of tumors. In most cases, surgery will not be able to remove all of the cancer but may be used if it can extend a person’s life and quality of life.

Drug Therapies

Traditional chemotherapy drugs are commonly used in combination therapy. These may include:

• Trexall (methotrexate)
• Velban (vinblastine)
• Adriamycin (doxorubicin)
• Platinol (cisplatin)

These drugs are cytotoxic, meaning they are toxic to living cells. They work by targeting fast-replicating cells like cancer. As a result of this action, they can also kill healthy cells that are fast-replicating, such as those in bone marrow, hair, and the small intestines.

Newer generation drugs work differently by stimulating the immune system to fight the cancer. Some examples include:

• Opdivo (nivolumab)
• Opdivo + Yervoy (ipilimumab)
• Tecentriq (atezolizumab)

These monoclonal antibodies are injected into the body. They immediately seek out cancer cells, binding to them and signaling other immune cells to attack.

This targeted form of immunotherapy can shrink tumors and prevent cancer from progressing. It is used primarily to extend the life of people with advanced, inoperable, or metastatic TCC. The most common side effects of these immune-stimulating drugs include:

• Fatigue
• Shortness of breath
• Joint or muscle pain
• Decreased appetite
• Rash
• Diarrhea
• Cough
• Constipation
• Rash or itchy skin
• Nausea

The combination of Opdivo and Yervoy has gained popularity in recent years in cases of advanced TCC. Treatment is given intravenously over 60 minutes, usually every two weeks. The dosage and frequency depend largely on how the cancer responds to the therapy and the severity of side effects.

Prevention

Prevention of TCC starts with factors you can control. Of these, cigarettes are key. The facts are simple: bladder cancer is the second most common smoking-related malignancy behind lung cancer. Quitting not only significantly reduces your risk of TCC but can prevent cancer recurrence once you've been successfully treated.

Quitting can be difficult and often requires several attempts. Most insurance plans, however, cover some or all of the cost of smoking cessation treatment.

Other modifiable factors can also contribute to a reduction in risk. One 10-year study involving 48,000 men found that those who drank 1.44 liters of water (roughly eight glasses) daily had a lower incidence of bladder cancer than those who drank less.

The findings were significantly limited since other factors like age and smoking were not considered. However, a 2014 meta-analysis suggested that black and green tea consumption offered a protective benefit, and for smokers, more fluid intake, in general, may help prevent bladder cancer.

While drinking water alone cannot erase the consequences of smoking, it does highlight the benefits of healthy lifestyle choices. These include proper hydration, physical activity, a healthy diet, and weight loss if you are obese.

Summary

Bladder cancer is one of the most common cancers in America. Most bladder cancers are transitional cell carcinomas (TCC).

TCC is slow growing and usually has no symptoms in the early stages. When symptoms do develop, they may include painful urination, blood in the urine, fatigue, and weight loss. 

Smoking is one of the largest risk factors for TCC. Other risk factors include older age, being male, and being obese. 

TCC has higher survival rates if caught in the early stages. It can also be prevented by quitting smoking and making important lifestyle changes, like staying hydrated and losing weight.