Bladder Cancer Stages, Symptoms and Treatment

The urinary bladder is the receptacle for urine excreted by the kidneys. The uncontrolled growth of cells marks the beginning of urinary bladder cancer. This condition is often associated with the infiltration of healthy tissues by the cancer cells. This cancerous spread is either localized to the bladder or metastasis to other parts of the body like the liver, lungs, and bones. People having bladder cancer usually have one or more tumors in their bladder.

Bladder cancer starts from the innermost layer of the bladder or mucosa and invades to the deeper layer as it progresses. It often appears as a papillary that is shrub-like in appearance but may sometimes appear as a nodule. It is more common in men than in women.

In India, bladder cancer accounts for 3.9 % of all cancer cases and is the country’s ninth most common cancer. The overall incidence rate of bladder cancer is 2.25 % of the entire Indian population. The age-standardized incidence rate is 3.67 per 100,000 males and 0.83 per 100,000 females in India.

Bladder cancer types :

The different types of bladder cancer are as follows :

  • Urothelial carcinoma: It is the most common type of bladder cancer and accounts for around 90% of the total cases. The type of cancer begins in the urothelial cells present in the inner lining of the bladder and is strongly associated with cigarette smoking. Urothelial carcinoma is also known as transitional cell carcinoma. It has two subtypes :
    • Papillary carcinoma – It is characterized by the presence of growing finger-like projections in the bladder lumen.
    • Flat carcinoma is characterized by the lack of finger-like projections in the bladder lumen.
  • Squamous cell carcinoma: Squamous cell carcinoma accounts for around 4% of bladder cancer and is mainly because of irritation and inflammation of the cell lining the bladder. If the irritation and swelling persist for a long time, then the squamous cells lining the bladder become cancerous. Long-standing bladder stones and chronic infections caused by the Schistosoma worm cause this type of cancer.
  • Adenocarcinoma: It is the most uncommon type, affecting only 2% of people with bladder cancer. It originates from the epithelial cells and is invasive. It is also associated with prolonged inflammation and infection of the bladder.
  • Other types: Small cell cancer arising from the neuroendocrine cells, pheochromocytoma, and bladder sarcoma are rare and uncommon types of bladder cancer.

Stages :

The different stage of bladder cancer are :

  • Stage 0 – The tumor is found on the bladder’s inner lining and not spread to the deeper layer of the bladder wall or towards the hollow part of the bladder. It is also known as carcinoma in situ.
  • Stage I – The tumor has grown through the bladder’s inner lining to the deeper layers but not to the bladder wall or the lymph nodes’ muscular layer.
  • Stage II – The tumor has spread to the bladder wall’s thick muscular layer but not to the fatty tissue surrounding the bladder or to the lymph nodes. It is also known as muscle-invasive cancer.
  • Stage III – Cancer has spread to the fatty tissue surrounding the bladder or to the prostate in men or vagina and uterus in women. It has also spread to the regional lymph nodes.
  • Stage IV – Cancer has spread through the pelvic wall or abdominal wall to the body’s distant parts and the lymph nodes located outside the pelvis.

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Symptoms :

  • Bleeding in the urine or hematuria that is usually gross, episodic, and painless
  • Pain in back
  • Painful and frequent urination
  • Urine incontinence
  • The urgency to pass urine
  • Pain in the abdomen
  • Difficulty in passing urine
  • Burning sensation while passing urine
  • Loss of weight
  • Loss of appetite
  • Fatigue
  • Swelling in feet
  • Pain in bones

Signs and symptoms of the advanced stage of the disease are :

  • Distended bladder due to tumor at the bladder neck
  • Inability to pass urine
  • Pain in the flanks due to obstruction of urine flow from the kidney to the bladder by the tumor
  • Bone pain
  • Cough or blood in the phlegm due to the spread of cancer to the lungs

Causes of bladder cancer 

Some factors that are known to cause bladder cancer are :

Abuse of tobacco– Patients consuming tobacco are 5 to 7 times more likely to develop bladder cancer than those who do not. Tobacco has multiple carcinogens that interfere with the host immunity and damage the bladder’s lining epithelium as these carcinogens are excreted in the urine.

Exposure to certain chemicals– Aromatic dyes, having benzene rings(aniline dyes, benzidine, beta-naphthyl amine) are irritants that lead to increased bladder proliferation epithelium, leading to disordered growth and finally a malignant change into cancer. These chemicals are commonly used in the leather, dye, and print industries. 

Radiation exposure– Radiations such as those from high dose ionizing radiations can lead to cancer of the bladder. Radiations cause a break in the DNA strands, leading to ineffective cell division. They also induce mutations that favor the cancer cells’ rapid proliferation and aid the cells to escape the body’s innate immune systems.

Chronic irritation and inflammation of the urinary bladder– Chronic irritation (physical or chemical or infective) leads to tissue injury. One of the characteristic responses of tissues to chronic injurious stimuli is metaplasia. This refers to replacing one cell type with another cell type and is often witnessed due to prolonged exposure to stress/irritation. Thus, the transitional bladder epithelium is replaced by squamous cells, and this is known as squamous cell metaplasia. Metaplasia, over long durations, favors the development of in-situ cancers. Bladder stones and infections may also increase the risk of bladder cancer.

Certain parasitic infection – Schistosoma hematobium, is a parasite that infects the bladder epithelium. It is a trematode/flat fluke and is often called a bladder worm. With the help of their suckers, they continuously attach and detach from the host, causing a chronic inflammatory reaction. A chronic inflammatory state decreases immunity, promotes cell proliferation, and consequently increases the risk for mutations and cancer. Also, the worms deposited in the bladder walls exacerbate the chronic inflammation and lead to neovascularisation (new blood vessel formation to rid the body of the parasite). This, in turn, increases the turnover of the epithelial cells of the bladder. 

Bladder cancer risk factors 

Smoking – Smokers are three times more likely to develop bladder cancer than non-smokers. Smoking cigarettes, cigars, and pipes cause the accumulation of more than 70 carcinogens in the urine. These carcinogens induce genetic mutations and promote cancerous development in a genetically susceptible host’s bladder.

Age – Older adults are at higher risk, but bladder cancer is also rarely diagnosed in people younger than forty years. Increasing age is a risk factor for the development of any cancer. As the telomerase shortening occurs at the ends of the chromosomes, there are increased chances of protein misfolding, changes in the DNA sequence, and a progressively diminishing immunity. Cancer is a multifactorial disorder of increased cell proliferation. Individuals above 55 years of age are more prone to developing bladder cancer.

Ethnicity / Race – European and European-American are at higher risk of developing bladder cancer. Western populations (Europeans and Americans) are prone to getting bladder carcinoma due to their changing lifestyle habits and the increasing incidence of other comorbid conditions like hypertension, diabetes mellitus, HIV-AIDS, and immunosuppression long term use of steroids that in turn impairs the immune responses.

Gender – Men are at higher risk than women as men have a genetic predisposition towards developing bladder carcinoma due to the increased prevalence of smoking as compared to women. Also, many males work in dye factories and other industries when they are continuously exposed to carcinogens, unlike women. This also accentuates their risk potential for bladder cancer.

Exposure to certain drugs – Cyclophosphamide, an anti-cancer drug, is responsible for causing bladder cancer as it is toxic to the bladder cells. Other chemicals like benzidine and beta-naphthylamine also increase the risk of developing bladder cancer. Pioglitazone, an anti-diabetic drug, is also prophesied to cause cancer, but it has not been conclusively proven.

People with a personal history of cancer – Bladder cancer has a high recurrence rate. Thus, even after surgery, cancer may develop again in some patients due to inadequate treatment or newly developed mutations. 

Family History – Persons who suffer from Lynch Syndrome or Hereditary Non-Polyposis Colorectal Cancer (HNPCC) may have an increased risk of developing bladder cancer (upper and lower tract). Individuals whose first-degree relatives are diagnosed with bladder cancer are at a higher risk.

Dietary Factors– Persons who consume a high-fat diet have a disturbed gut microbiota, and thus their gut-associated lymphoid tissue immunity diminishes. It can predispose the individual to abdominal infections that may also reach the bladder. Furthermore, decreased or reduced water intake alters the concentration of urine, and this may cause stones to precipitate or result in the accumulation of toxins. This eventually leads to the bladder’s irritation, obstruction, and inflammation and thereby increases the risk of cancer of the bladder.

Diagnosis 

The following tests and exams diagnose bladder cancer:

  • Urinalysis – This is a simple urine test that is usually the first test recommended by the doctor to check if there is any bleeding in the urine or not. Although it doesn’t confirm bladder cancer, it helps to list out the possible causes of bleeding in the urine. 
  • Urine cytology – It is used to look for abnormal cells in the urine. In this test, the urine sample is centrifuged and then examined by a pathologist under a microscope. This test has a diagnostic accuracy of 95 % for advanced-stage bladder cancer, while that for early-stage cancer is 15 %.
  • Ultrasound uses sound waves to detect tumor presence in the bladder and detect swelling in the kidneys, primarily if this is associated with the bladder tumors. It is also used to detect the other potential causes of bleeding in the urine, such as prostate enlargement or stones in the urinary system.
  • Computed tomography (CT) scan and Magnetic resonance imaging (MRI) helps visualize the bladder and help detect small tumors in the bladder and kidney. By the use of intravenous contrast, these scans help to accurately identify if the tumor is responsible for the bleeding in the urine or not.
  • Cystoscopy – A cystoscope or thin tube-like optical instrument connected to a camera and light source is passed into the urethra to capture images of the bladder and visualize the inside of the bladder. Small and flat tumors are made visible by this method, and it can also be used to collect a sample of the tissue for biopsy.
  • Biopsy – A small sample of the tissue collected from the bladder’s suspicious site by using a cystoscope is sent to the pathologist for microscopic examination. It provides a definite diagnosis for the presence of bladder cancer.
  • NMP 22 and fluorescent in-situ hybridization are newer techniques used to detect bladder cancer cells in a simple urine test. Their accuracy level is less compared to that of urine cytology and cystoscopy.

Treatment 

Bladder cancer treatment depends on the stage and the patient’s overall health condition. The most commonly adopted treatment options are :

  • Transurethral surgery is the primary treatment that one undergoes following a definite diagnosis of bladder cancer. Special instruments are attached to the cystoscope for performing this surgery. This helps to cut the tumor and remove it from the bladder with an electrical cautery device. It is done via the normal urine passage and does not involve any cuts. This surgery can also be used to stage bladder cancer.
  • Intravesical therapy – This therapy is done within 6 to 24 hours of transurethral resection of the bladder tumor to kill any leftover cancer cells. In this, liquid drug-like mitomycin is put into the bladder using a soft catheter, and this drug stays in the bladder for 2 hours. This drug affects the cells that line the bladder and does not affect the deeper layers of the bladder wall.
  • Chemotherapy – drugs like cisplatin, mitomycin with 5- fluorouracil, and cisplatin with fluorouracil are often used in combination with radiation therapy for treating bladder cancer. The most common combination of chemotherapeutic drugs recommended for treating bladder cancer without radiation includes gemcitabine with cisplatin, gemcitabine with paclitaxel and cisplatin, methotrexate, and vinblastine (CMV), among others. These drugs are given for weeks and are most commonly used for squamous cell carcinoma.
  • Radiation therapy – High energy x-rays produced by machines are often used to treat bladder cancer. It is often recommended for people diagnosed with earlier cancer stages and cannot undergo surgery or chemotherapy. It is done 5 days a week for several weeks.
  • Immunotherapy – Use of BCG or Bacillus Calmette-Guerin is the most common intravesical immunotherapy that stimulates the bladder’s immune cells to attack the cancer cells. Immune checkpoint inhibitors like atezolizumab, avelumab, nivolumab, and pembrolizumab target the PD-1 protein on the cancer cells to shrink the tumors or slow their growth. Monoclonal antibodies like enfortumab vedotin are also used to treat people with advanced bladder cancer. 
  • Targeted therapy – Specific genes, proteins, and receptors are targeted to slow down the cancer cells’ growth and destroy them. Fibroblast growth factor receptor (FGFR) inhibitors like erdafitinib target the FGFR2 or FGFR3 gene to treat locally advanced or metastatic bladder cancer.

Complications 

  • Pain
  • Depression
  • Significant anxiety
  • Nutritional deficiency
  • Metastasis of cancer
  • Swelling of the ureters
  • Mood swings
  • Removal of the urinary bladder
  • Erectile dysfunction in men
  • Narrowing of the vagina in women

Lifestyle changes to prevent urinary bladder cancer :

  • Avoid tobacco and secondhand cigarette smoke.
  • Limit exposure to cancer-causing chemicals at work
  • Drink plenty of fluids, mostly water.
  • Eat healthy food. Avoid fatty food
  • Exercise daily.
  • Eat plenty of fruits and vegetables.
  • Avoid food that has an artificial color.
  • Get treated for any inflammation and irritation of the urinary bladder.
  • Avoid getting contaminated with the parasite while traveling.

FAQs 

  1. Is it curable?
  • Bladder cancer is mostly curable as it is diagnosed in the early stages, but recurrence chances are high if proper follow-up treatment is not adopted. If cancer has spread to the other parts of the body and lymph nodes, then chances of complete recovery are slim, but it can be managed by using palliative care.
  1. What are the survival chances of bladder cancer? The 5- year survival rate for bladder cancer is 80 % when it is detected in the early stages. The survival rate for bladder cancer that has spread to regional lymph nodes is 36.3 %, while the survival rate when it spreads to other parts of the body is 4.6 %.
  1. What is the cost of treatment for bladder cancer in India? The average cost of bladder cancer surgery is around 4 to 8 lakhs, while that for chemotherapy per cycle is around 1 lakh.
  1. What hospitals to get treatment in India?
  1. Is bladder cancer hereditary? Bladder cancer is usually not hereditary but is most often associated with acquired genetic mutations. Although some people inherit genetic mutations that may cause bladder cancer, this does not seem to be a major cause of the disease as the disease manifests only if other environmental factors are supportive.

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