What Is Transitional Cell Carcinoma (TCC)?

Urothelial carcinoma, the most common form of bladder cancer, linked to smoking

A doctor discusses a new diagnosis with an older male patient.
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While bladder cancer is not a type of cancer we speak about as much as, say, lung cancer, breast cancer, or melanoma, it is, in fact, the fourth most common cancer in American men and the ninth most common in American women. According to data from the Centers for Disease Control and Prevention, over 55,000 men and 17,000 women get bladder cancer in the U.S. every year. Of these, nearly 16,000—over one in four—will die as a result of a malignancy.

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, aptly, the transitional urothelium.

TCC can develop in tissue from anywhere along the 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 considered the second most common cause of kidney cancer when involving the renal sinus.

Signs and Symptoms

Symptoms of TCC will vary by the location of a tumor. They often times resemble symptoms of a severe kidney infection wherein a person will experience painful urination and lower back/kidney pain. Because the disease mimics so many other possible causes (including cystitis, prostate infection, and overactive bladder), diagnoses tend to be made when the cancer is more advanced.

At the same time, TCC is a slow-developing cancer with a latency period of anywhere up to 14.5 years, according to the National Cancer Institute. In the earlier, precancer stage, symptoms can often be vague to nonexistent. It is typically only when a malignancy is advanced that many of the more tell-tales appear.

It is for these reasons that 89 percent of diagnoses are made in men 50 and over. Of these, 20 percent will be diagnosed with stage III cancer, while nearly one in four will have metastatic disease (where the cancer has spread to other parts of the body).

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 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

People will often assume that cancer of the bladder or kidneys is caused by exposure to toxins we ingest, whether it be contaminated water or chemicals in our food. For the most part, this is not the case. While toxins are definitely linked to the development of TCC, they are most often the types we inhale over long periods of time.

Chief among these is cigarette smoke. In fact, over half of all TCC diagnoses in men and over a third in women are associated with heavy 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.

According to research from the Memorial Sloane-Kettering Cancer Center in New York, bladder cancer in smokers is not only more prevalent but usually more invasive than 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 epithelial tissues which give rise to lesions and cancers. The risk is seen to be highest in persons who smoke over 15 cigarettes a day.

Other risk factors to TCC include:

  • Older age, with around 90 percent of cases occurring in persons over 55
  • 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, increasing risk by 10 to 20 percent
  • Workplace exposure to aromatic amines used in the dye and printing industries as well as in the manufacture of rubber, leather, paint, and textile 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

Generally speaking, the first diagnostic indication of TCC will be blood in urine. Sometimes it will not be visible but can be easily detected in a urinalysis (urine test).

A urine cytology can also be used to look for cancer cells in urine, although this is a less reliable form of diagnosis. By contrast, newer technologies can identify proteins and other substances in urine associated with TCC. These include tests popularly known called Urovysion and Immunocyt. There is even a prescription home test known as Bladderchek which 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 by cystoscopy. The cystoscope is a long flexible tube equipped with a micro-camera which is inserted into the urethra to view the bladder. A biopsy involves the extraction 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. It is not uncommon to use general anesthesia in men as the procedure can be extremely painful given that the male urethra is longer and narrower than in women.

Cancer Staging

If a cancer diagnosis is made, the oncologist will classify the malignancy by stage. The doctor will do so using the TNM staging system which describes the size of the original tumor ("T"), the infiltration of cancer into nearby lymph nodes ("N"), and the extent of metastasis ("M").

The aim of the classification is to determine the appropriate course of action with aim of neither undertreating nor overtreating the cancer. Based on these findings, the doctor 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 epithelial lining 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, spread to nearby lymph nodes, or both.

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

With that being said, earlier diagnosis is almost always associated with better outcomes. Persons diagnosed with stage 0, stage I, or stage II TCC have 90 percent likelihood of a cure. Those with stage III have a 50 percent chance. Even those with stage IV cancer have a 10 percent and 15 percent chance of a sustained remission, according to the National Cancer Society.

Treatment Approaches

Treatment of TCC is largely dependent on the stage of the disease, the extent by 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. Among them:

  • Stage 0 and I tumors which have not yet reached the muscle layer can often be “shaved off” with an electrocautery device attached to the end of a cystoscope. The procedure may be followed with a short course of chemotherapy. Immunotherapy treatments using a vaccine known as Bacillus Calmette-Guérin (BCG) can also lessen the risk of recurrence in two out of three cases.
  • Stage II and III cancers are more difficult to treat. They would require extensive removal of any affected tissue. In the case of the bladder, it may require 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 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 as well as the quality of life.

Drug Therapies

Traditional chemotherapy drugs such as methotrexate, vinblastine, doxorubicin, and cisplatin are commonly used in combination therapy. They are cytotoxic (meaning toxic to living cells) and 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 those in bone marrow, hair, and the small intestines.

Newer generations drugs like Opdivo (nivolumab), Yervoy (ipilimumab), and Tecentriq (atezolizumab) work differently by stimulating the immune system to fight the cancer. These so-called monoclonal antibodies are injected into the body and 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 the cancer from progressing. They are 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 the factors you can control. Of these, cigarettes remain the key focus. The facts are simple: bladder cancer is today the second most common smoking-related malignancy behind lung cancer. Quitting not only significantly reduces a person’s risk of TCC but can prevent cancer recurrence in those successfully treated.

Quitting can be difficult and often requires several attempts, but most insurance plans today 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 in 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 compared to those who drank less. While there remain significant limitations as to the findings (given that other factors, such as smoking and age, were not included), a 2012 meta-analysis did suggest that fluid intake offered a protective benefit, particularly in younger men.

While drinking water alone cannot erase the consequences of smoking, it does punctuate the benefits of healthy lifestyle choices which include proper hydration and a structured weight loss program if obese.

Sources:

American Cancer Society. "Treatment of Bladder Cancer, by Stage." Atlanta, Georgia; update May 18, 2017.

Burger, M.; Catto, J.; Dalbagni, G.; et al. "Epidemiology and risk factors of urothelial bladder cancer." Eur Urol. 2013; 63(2): 34-41. DOI: 10.1016/j.eureo.2012.7.033.

Centers for Disease Control and Prevention. “"Bladder Cancer." Atlanta, Georgia; updated June 6, 2017.

Jiang, X.; Castaleo, J.; Yuan, J. et al. "Cigarette Smoking and Subtypes of Bladder Cancer." Int J Cancer. 2012;130(4):896-901. DOI: 10.1002/ijc.26068.

National Cancer Institute: National Institutes of Health. "Bladder and Other Urothelial Cancers Screening (PDQ)–Health Professional Version." Washington, D.C.; updated February 22, 2017.

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