Bladder cancer (bladder tumor) is a type of cancer that develops from the transitional epithelial cells lining the inner surface of the bladder. It is the second most common type of cancer among urinary system cancers, after prostate cancer. It is seen more frequently in men. Smoking and chemicals are important in the emergence of the disease. Early diagnosis is possible due to bleeding in the urine. Treatment varies depending on the stage of the disease. In this article, I will give general information about bladder cancer with the help of my own experiences and the literature.

What is bladder cancer?

The bladder is an organ where the urine filtered from the kidneys is stored until the urge to urinate. Bladder cancer is a malignant disease that arises from the cells in the layer called “urothelium” (urothelial cells, transitional cells, transitional epithelial cells) that line the inner part of this organ. Although urothelial cells are mostly found in the bladder, they also cover the structures called calyces inside the kidneys, ureters and the inner layer of the urethra.

What are the types (types) of bladder cancer?

Bladder tumors mostly develop from the transitional cell epithelium lining the inner part of the bladder. In addition, it may originate from other cells. Bladder cancer pathologically arises from the following cells:

• Urothelial cancer: Urothelial carcinoma was formerly known as transitional cell cancer (TCC). This cancer arises from the cells lining the inside of the bladder. These cells also line the inner part of the ureter, bladder and urethra. Urothelial cancers are the most common cancer of the bladder.
• Squamous cell cancer: This type of cancer develops as a result of chronic irritation of the bladder. Bladder stones and long-term catheter use are the most common causes of irritation in the bladder. This form of cancer is common in Egypt as a result of infection with the Schistosoma parasite.
• Adenocarcinoma: It develops from mucus-secreting cells in the bladder. It is an extremely rare bladder cancer. Adenocarcinomas are cancers that are resistant to chemotherapy and drug therapy. The most effective treatment is surgery. It is seen in as low as 1% of bladder cancers.
• Others: Sarcoma and small cell bladder cancers are less common.

Staging of bladder cancer

After a diagnosis of bladder cancer is made, the extent of spread of the disease, that is, metastasis, is investigated. This is very important because treatment is planned according to the stage of the disease. We stage bladder cancer according to the widely used TNM staging. Here, T indicates primary tumor, N indicates lymph node involvement, and M indicates metastasis. We stage bladder tumors as follows:

Stage 0: In this stage, there are no metastases in lymph nodes or distant organs. Stage 0 is divided into two groups:

• Stage 0a: There may be one or more papillary type cancers in the bladder. The cancer is limited to the superficial epithelial layer and has not invaded deeply.
• Stage 0is: There is no papillary type growth into the bladder, but cancer cells with superficial cells growing horizontally. This is called “carcinoma in situ”. The course of these cancers is more aggressive.

Stage 1: Here, the cancer has spread to the layer below the superficial epithelial layer (subepithelial layer). There is no involvement in the muscle layer. At this stage, there are no lymph nodes or distant organ metastases.

Stage 2: At this stage, the cancer has advanced to the bladder muscle (detrusor muscle) layer. The cancer has not spread to the lymph nodes or other organs.

Stage 3: This stage is divided into two groups;

• Stage 3A: Cancer has invaded the fatty layer deep within the bladder muscle or surrounding organs (prostate in men, vagina in women). There is at most 1 metastasis in the regional lymph nodes of the bladder. There is no distant organ or lymph node metastasis.
• Stage 3B: The tumor has metastasized to many pelvic or upper pelvic lymph nodes. There is no involvement in distant organs or lymph nodes at levels above the common iliac vessels.

Stage 4: This stage is divided into two groups;

• Stage 4A: At this stage, bladder cancer has spread to distant lymph nodes above the iliac vessels, but there is no involvement of the organs.
• Stage 4B: The bladder tumor has metastasized to other organs such as bone, lung, and liver.

Grading system of bladder cancer (pathology)

Pathology is very important in bladder cancer. All parts taken during surgery are subjected to pathological examination and treatment planning is made according to this result. Pathologically, bladder cancer is divided into 2 grades based on examination under a microscope:

• Low-grade bladder cancer: Low-grade cancer cells look similar to normal cells. In these cases, spread into the bladder muscle and other organs of the body is extremely rare.
• High-grade bladder cancer: Here, cancer cells are very different from normal cells, the normal cell appearance has disappeared, this is also called “poorly differentiated” cancer. These spread more quickly to the bladder muscle and distant organs than low-grade cancers.

What are the causes and risk factors of bladder cancer?

The causes of bladder cancer are very different. Many factors, from genetic factors to environmental factors, play a role in the formation of cancer. Factors and risk factors that play a role in the development of bladder cancer are:

• DNA mutation in urothelial cells: Cells that undergo mutation (abnormal change) for various reasons multiply rapidly and over time, spread outside the bladder and metastasize (spread).
• Smoking: Bladder cancer is common in those who smoke cigarettes or cigars and those who are in closed environments where they are smoked. While many carcinogenic substances found in cigarettes are excreted through urine, they damage the cells in the bladder and cancer develops over time. Bladder cancer should be considered when a person who smokes for a long time has painless urinary bleeding.
• Age: Bladder cancer is most common after the age of 55. It may also happen in earlier periods. Smoking, genetic and environmental factors predispose to the development of the disease at an earlier age.
• It is more common in men: Bladder cancer is more common in men than in women. The fact that smoking is more common in men may be effective in this.
• Exposure to some chemicals: Kidneys are important organs that filter harmful substances from the body and excrete them through urine. Among the chemicals, “arsenic” is very important. Bladder cancer is common in people working in the textile, rubber, leather, shoe industry and printing industry.
• Some chemotherapy drugs: The chemotherapy drug called cyclophosphamide is used in the treatment of some cancers. While its breakdown product in the liver (acrolein) is excreted in the urine, it damages the cells in the bladder and causes cancer to develop.
• Radiation: Bladder cancer may develop later in those who receive radiation therapy due to cancer in the organs around the bladder (such as large intestine, ovarian, uterine cancer in women).
• Chronic bladder inflammations: The risk of bladder cancer increases in cases of chronic, frequently recurring infections (cystitis) and long-term use of catheters (paralyzed patients).
• Schistosoma infection: Bladder cancer may develop as a result of bladder infection with a parasite called schistosoma. This disease is most common in Egypt.
• Having a family history of bladder cancer: The risk of bladder cancer is higher in those whose first-degree relatives have bladder cancer.
• Lynch syndrome (hereditary nonpolyposis colorectal cancer) (HNPCC): In this syndrome, cancer can be seen in organs such as the urinary system, colon (large intestine), uterus and ovaries.
• Diabetes: All types of cancer are common in diabetic patients. Bladder cancer is one of them.

• Obesity: Obesity is a risk factor for cancer. It is very important for patients to reach their ideal weight by exercising and dieting regularly against cancer.

What should be taken into consideration to prevent bladder cancer?

Cancer prevention is very important. People need to be made aware of this issue. To protect yourself from bladder cancer, staying away from causes that may cause cancer is the most effective method of prevention. We can list them as follows:

• Quit smoking: Smoking is a very important cause of bladder cancer. For this reason, smokers must definitely quit smoking. In addition, even if they do not smoke, those who are in closed environments where smoking is allowed (passive smokers) are at serious risk, so it is very important for them not to enter these environments in order to protect themselves from bladder cancer.
• Attention should be paid to environmental chemicals: Precautions should be taken against important environmental factors that may cause bladder cancer and these environments should be avoided.
• A diet based on vegetables and fruits: It is very important to eat mainly fresh fruits, vegetables and antioxidant vitamins instead of animal products. It is necessary to avoid eating Western-style foods rich in animal products. Mediterranean diet is protective against bladder cancer.
• Screening and early diagnosis: It is important for those with cancer in the family to be checked at regular intervals in order to catch the disease early. In this way, there is no need for more aggressive surgical interventions.

• Weight control: Helping obese patients reach their ideal weight through a regular diet and exercise program plays a preventive role in the emergence of cancer. We recommend our obese patients to lose weight, especially if there is cancer in the family.
• Exercising regularly: A sedentary life causes many diseases, including cancer. A regular and active life is protective against cancer. We recommend a more active lifestyle to our patients instead of a sedentary one.

What are the signs (symptoms) of bladder cancer?

Bladder cancer shows symptoms in the early stages with bloody urine. Sometimes, if the disease has spread outside the bladder, that is, if there is metastasis, there may be symptoms related to this. The most common symptoms of bladder cancer or the reasons why patients consult a doctor are:

• Hematuria: Hematuria means blood in the urine. There are two forms of hematuria: Microscopic, that is, bleeding that cannot be seen with the naked eye, but can be seen under a microscope. The second is macroscopic hematuria. Here, patients go to the doctor due to visible bleeding while urinating. Bleeding in bladder cancer is usually a painless, clotted bleeding that stops and starts again from time to time.
• Frequent urination: Since the capacity of the bladder will decrease due to bladder cancer, patients will urinate frequently.
• Burning during urination: Painless bleeding occurs in bladder cancer, but if patients also have an infection, there may be pain during urination or as a result of blood clots blocking the urinary tract.

• Back pain: Back pain may occur in the advanced stages of the disease, as a result of swelling in the kidneys as a result of the cancer affecting the urinary ducts leading to the bladder. Or it may be the result of cancer spreading to the bones or compression of nerve roots.
• Bloody sputum, cough: If bladder cancer affects the lungs, cough and bloody sputum are observed.
• Bone pain: Pain occurs in the bones as a result of the spread of cancer to the bones.

Diagnosis of bladder cancer

In order to diagnose bladder cancer, examination of patients, anamnesis (medical interrogation), laboratory tests and radiological diagnostic methods are used. There is no tumor marker used to diagnose bladder cancer in advance or for postoperative follow-up.

• Medical history: Patients are asked whether their first-degree relatives have cancer. Smoking, chemical exposure, occupational and environmental factors are also investigated.
• Symptoms: Patients who are considered to have bladder cancer are asked about the symptoms related to these diseases. The onset and degree of symptoms are investigated. The most important of these is painless macroscopic hematuria (visible red blood in the urine).
• Cystoscopy: With a method called cystoscopy, the bladder is entered and examined with a camera. During cystoscopy, the location, number and size of cancer in the bladder and whether it involves the ureter orifices are evaluated. A short-term anesthesia is given. Cystoscopy is a 15-minute procedure. The patient is discharged on the same day.
• Biopsy: During cystoscopy, the tumor in the bladder is resected (cut out) with a tool called resectoscope. The removed piece is sent to pathology and detailed treatment planning of the disease is made.
• Urine microscopy: Hematuria may be seen in microscopic examination in patients with bladder cancer.
• Urine cytology: It is the examination of cancer cells under a microscope in a urine sample taken from the bladder. An experienced pathologist is required to detect cancer with this method. Cytology is also used in the follow-up of cancer patients.
• CT urogram: Cancer in the urinary system and bladder is evaluated by administering contrast materials.
• Ultrasonography: Cancer in the bladder and the condition of the kidneys (hydronephrosis, swelling) are evaluated.
• MRI: Shows the spread of the disease to surrounding tissues and lymph nodes.
• PET-CT: With this method, it is possible to show that the disease has metastasized to bones and other parts of the body.
• Retrograde pyelography: Under cystoscopy, contrast substances are administered through the bladder orifice via a catheter and the ureters, renal pelvis and calyces are visualized.
• IVP: The condition of the kidneys is evaluated by administering medication intravenously, and the calyces, ureter, renal pelvis and bladder are visualized.

Treatment of bladder cancer

In the treatment of bladder cancer, the type of cancer, grade, stage and the general health of the patient should be taken into consideration. Treatment options for bladder tumor patients include:

• Surgery (surgery)
• Giving medication into the bladder
• Systemic chemotherapy
• Radiotherapy
• Immunotherapy
• Targeted therapy

Bladder cancer surgery: The gold standard diagnosis and treatment method that should be performed first in patients with bladder cancer is TUR surgery, which is performed by the closed method. Different surgical methods can be applied after pathological examination of the parts taken at the end of the TUR. The main surgeries performed in bladder cancer are:

• Transurethral bladder tumor resection (TUR-M): It is an operation to enter the bladder endoscopically and remove the cancer, where there is no incision anywhere in the body. During TUR surgery, cancer tissue is removed deeply, including the muscle layer. The muscle layer is important because when examining the cancer tissues taken, if there is bladder muscle, the entire bladder must be removed. If there is no muscle layer, it means that sufficient TUR has not been performed. If all the cancer has been removed with TUR and no cancer is seen in the muscle tissue, there is no need to remove the bladder and drugs are administered into the bladder to prevent the cancer from recurring.
• Cystectomy: Cystectomy is performed in 2 ways: Radical cystectomy and partial cystectomy. Cystectomy surgery can be performed open, laparoscopically and robotically.
• Radical cystectomy: Radical cystectomy is the removal of the entire bladder and lymph nodes. In addition to these, in men, the prostate, seminal vesicles and some of the seminal ducts are also removed. In women, the uterus, ovaries, tubas and the upper part of the vagina are removed.
• Partial cystectomy: Not the entire bladder, but only some healthy tissue surrounding the cancerous part is removed.
• Neobladder surgery (artificial bladder, orthotopic bladder, ileal neobladder, intestinal bladder): After the bladder is removed, a piece of approximately 50 cm is taken from the small intestine to make a bladder and replace the removed bladder. The ureters are connected to the artificial bladder, allowing urine to be collected there, and the lower part of the artificial bladder is connected to the urethra, allowing urine to be expelled. In this surgery, the patient does not carry a bladder in his abdomen and continues his life like a normal person.
• Ileal loop or ileal conduit: In this surgery, after radical cystectomy, a 15-20 cm piece of the small intestine is taken and the ureters (ducts that bring urine from the kidney to the bladder) are connected to one end, and the other end is connected to the abdominal wall. In this surgery, patients live by attaching a urine bag to the part of the intestine that connects to the abdomen, and when the bag is full, it is emptied. No urine comes from the normal urinary tract (penis), patients continue their lives with a bag.
• Continent urinary reservoir: Here, after the bladder is removed, a piece of 40-50 centimeters taken from the intestines is shaped into a pouch and placed in place of the normal bladder, one end is connected to the outer part of the abdomen, a valve mechanism is made here to prevent the urine from flowing continuously, the patient passes through this hole opened to the outside for certain periods of time. urinates with a catheter.

Chemotherapy: Chemotherapy is the process of giving drugs to kill cancer cells. Chemotherapy for bladder cancer is given in 2 ways:

• Systemic chemotherapy (iv, intravenous chemotherapy): It may be given before surgery to kill cancer cells, this is called neoadjuvant chemotherapy. If it is given to destroy cancer cells remaining in the body after the bladder is removed, this is called adjuvant chemotherapy. These chemotherapy protocols are usually given in 3-4 cycles, and radiotherapy (radiation therapy) may also be added. Chemotherapy regimens often use more than one drug.
• Intravesical chemotherapy (Giving medication into the bladder (intravesical or intracavitary chemotherapy): If there are no cancer cells in the bladder muscle after bladder cancer is removed with TUR surgery, in such cases, medication is given into the bladder 10-15 days after the surgery to prevent the cancer from recurring. In this way, cancer recurrence is prevented. If only TUR is performed without medication, approximately 70-80% of these cases recur. Therefore, intravesical chemotherapy should be applied to some patients to prevent relapses. This treatment is a long-term treatment.

Radiotherapy: Radiotherapy is a treatment method that aims to kill cancer cells with radiation rays. In some cases, radiotherapy is given together with chemotherapy. Radiotherapy is administered by the radiation oncology department. The required amount of radiation and duration are adjusted according to the condition of the disease.

Immunotherapy: Immunotherapy aims to stimulate the body’s immune system to fight cancer and kill cancer cells. Immunotherapy is applied in 2 ways:

• It is administered directly into the bladder (intravesical therapy); After TUR surgery, it is applied inside the bladder in cancers that do not extend to the bladder muscle. BCG is most often given for this purpose. BCG activates local immune system cells in the bladder, killing or destroying cancerous cells.
• It is given intravenously: In advanced cancer cases, chemotherapeutic drugs given intravenously destroy cancer cells by stimulating the immune system.

Targeted therapy in bladder cancer: The drugs used in this treatment are effective by affecting certain mechanisms within cancer cells. They are used to eliminate cancer cells in advanced cancer patients when other treatment options are not effective.

Control of bladder cancer patients

Even if bladder cancer is treated very effectively, it may recur in later periods, so these patients should be checked very regularly throughout their lives. The best method for checks is cystoscopy. Patients should be checked with cystoscopy every 3-6 months, depending on the degree of the disease. These control periods may be extended in later periods. If the cancer is high-grade, check-ups should be done more frequently. In general, after TUR surgery, we check our patients with cystoscopy every 3 months for the first year, every 6 months for the second year, and every year for up to 5 years after the 3rd year. Control protocols suitable for other treatment methods should also be applied and necessary treatments should be planned.

In summary: Bladder cancer is a malignant disease of the urinary bladder. It is common in men. Smoking is the most important factor. Painless bloody urination is the most important symptom of the disease. Appropriate treatment is given according to the stage of the disease. We have been successfully performing TUR-T surgery, radical cystectomy and artificial bladder surgery on patients with bladder cancer for a long time. Regular follow-up and care of these patients is very important.

Prof. Dr. Emin ÖZBEK

Urology Specialist

Istanbul- TURKEY