Bladder cancer is the most common cancer of the urinary system. It is quite common throughout the world with the US alone reporting 79, 030 cases and 16, 870 deaths in the year 2017. In developing nations like India and other countries in South East Asia, this risk is almost twice as high as per review from the PubMed library. This significantly states the need for early diagnosis and treatment.

Risk Factors for Bladder Cancer

Age, Gender and Ethnicity

Older age individuals especially males are generally at increased risk of developing bladder cancer with most of the incidences observed in the 6th, 7th, and 8th decades of life.

Tobacco/Cigarette smoking

Use of tobacco is one of the major risk factors for bladder cancer with the higher risk involved for more amount used over a short duration. Smokers are at 3 times higher risk of developing bladder cancer compared to non-smokers. The incidence increases with the intensity and duration of smoking.

Family history

Risk of developing bladder cancer increases in an individual with a history of bladder cancer in first-degree relatives (parents, brother, sister, or child). Previous history of bladder cancer in the family may increase the risk in other family members.

Genetic Cancer Predisposition Syndromes

Following are some examples:

• Lynch syndrome or hereditary non-polyposis colorectal cancer (HNPCC, generally caused by a mutation in the MLH1 or MSH2gene);
• Cowden disease (caused by a mutation in PTEN/MMAC1 gene); and
• mutations in retinoblastoma (Rb1), SLC14A1 (a urea transporter gene), GSTM1, and NAT2.
  

Personal History

Individuals with a personal history of cancer in the lining of any part of the urinary tract are generally at higher risk of developing another cancer.

Occupational exposure

Higher risk of bladder cancer is also associated with regular exposure to certain chemicals like paint, dye, heavy metals, or petroleum products generally experienced by dyestuffs workers, painters, leather workers, truck drivers, aluminum workers and workers in the dry-cleaning industry.

Previous Treatments

History of exposure to radiation and treatment with certain drugs like cyclophosphamide, ifosfamide, phenacetin, and pioglitazone is reported to be the independent risk factors for bladder cancer.

Infection/Inflammation

Infection with Schistosoma haematobium (a parasitic worm that is prevalent in certain parts of Africa and the Middle East) is associated with an increased risk of bladder cancer.

Exposure to a high level of arsenic or chlorine in drinking water can also increase the risk of bladder cancer.

Chronic irritation of bladder

Chronic irritation by urinary tract infection, kidney/bladder stones, or prolonged use of catheters have also been linked to a high incidence of bladder cancer.

Other Factors

Diabetes mellitus (especially type 2 diabetes), heavy alcohol consumption, high intake of coffee/tea, artificial sweeteners, and low intake of water are some other risk factors postulated for bladder cancer.

Bladder Cancer Symptoms and Signs

But, how will you seek treatment if you don’t suspect bladder cancer in the first place? To meet this gap, we will introduce you to the symptoms of bladder cancer so that you can easily speculate your risk.

Bladder cancer may present with any one or more of the signs or symptoms mentioned below. These may vary depending on the extent of disease, location of bladder tumor, site of metastasis, etc.

Sometimes, other conditions may present in a similar manner. So, it is important to consult your doctor if you notice any of these symptoms and undergo thorough testing.

Early Symptoms of Bladder Cancer

Blood in Urine (Hematuria)

In most cases, haematuria is the first sign of advanced bladder. It may in the form of microscopic or gross hematuria. Microscopic haematuria is the presence of blood in urine, which may not be visible to your naked eye. Gross hematuria is, the presence of blood in your urine, which will be very much visible to the naked eye. It may be in the passage of blood clots in urine in some cases. In other cases, it may simply be seen as change in the colour or your urine to a reddish colour.

The American Cancer Society classified this colour to be ranging from orange or pink to red and dark red, the latter being relatively uncommon.

You must note that you need not wait until you notice blood in your urine each day before suspecting bladder cancer. You may notice it on a day and then may not see it again for months. In most cases, there will be very little to no pain.

Increased Frequency of Urination (Poluuria)

You may feel the urge to feel more often than usual. Maybe at every hour or several times of the day. Further, you may repeatedly wake up at night to urinate or may face difficulty in sleeping because of frequent awakenings due to this desire.

It may be due to the bladder mass obstructing the urine flow causing incomplete emptying of the bladder. It may also be due to urinary tract infection causing bladder irritation leading to frequent passing of urine.

Burning or Painful Urination

Burning urination may be due to urinary tract infections, occuring as a result of long term retention of urine in bladder. This may be associated with increased frequency of urination also.

Painful urination and difficulty in urinating despite the presence of desire to urinate may occur due to bladder neck mass causing obstruction in the flow of urine.

General Symptoms

Constitutional symptoms like fatigue, weight loss, loss of appetite and/or diminished desire to participate in daily activities such as going to work, exercise, etc may occur as a result of bladder cancer or coexistent urinary infections.

Symptoms of Late or Advanced Stage Bladder Cancer

Late stages of bladder cancer include cases with locoregional involvement of nearby structures and distant spread of the tumor. In addition to ones mentioned above, these may be one or more of the following-

Heaviness or Pain in Abdomen

Presence of a lower abdominal or pelvic mass, which may or may not be painful may be an indication of bladder cancer that has spread to surrounding areas. Or else, it may occur due to the spread of cancer to lymph nodes in lower abdomen.

Involvement of intestine may cause intestinal obstruction leading to constipation and feeling of heaviness in abdomen or bloating sensation.

Obstruction to the flow or passage of urine may cause bladder fullness that may cause discomfort in the pelvic region. Sometimes, bladder mass close to vesico-urteral junction may cause hydronephrosis and pain in back or loin region.

Jaundice

Spread of bladder cancer to liver may cause jaundice or yellowish discoloration of eyes and/or urine. It may sometimes be associated with pruritus or generalised itching over the body.

Breathlessness or Cough

Breathing difficulty, excessive coughing and/or pain on deep breathing may be a sign of bladder cancer spread to lungs or pleura (causing fluid accumulation around the lungs).

Pain at Bony Sites

Sometimes, spread of bladder cancer to one or more bones may cause pain in back, ribs, etc.

Can Bladder Cancer be mistaken for UTI?

Urinary tract infection is one of the commonest benign differential diagnosis of bladder cancer. As we have already discussed above, early symptoms of bladder cancer such as increased frequency of urination, nocturia, burning sensation during passage of urine are the most common symptoms of urinary tract infections also.

Moreover, microscopic or macroscopic hematuria may also be seen in some cases of UTI.

So, bladder cancer, especially in early stages could easily be mistaken for UTI. A high level of suspicion and adequate diagnostic work-up is very important to differentiate between the two.

Bladder Cancer Diagnosis

When someone is suspected of bladder cancer based on presence of signs or symptoms, certain diagnostic investigations are required to confirm and stage the disease.

These diagnostic tests discussed below help us confirm the presence of bladder tumor, and also other details, like type of tumor, number, depth of invasion, involvement of regional lymph nodes, and spread to distant sites.

All this information helps the oncologist to take an appropriate treatment decision. The infographic below lists some of the investigations.

Urine Tests for Tumor Markers

With the advancement of science, newer tests are now available to check the presence of certain markers in the urine which may suggest bladder cancer. For example, Telomerase (an enzyme usually found in cancer cells), bladder tumor-associated antigen (BTA), carcinoembryonic antigen (CEA), and NMP22 protein. But these tests are not very reliable and may provide with a supportive evidence of the tumor.

Cystoscopy

Cystoscopy is a diagnostic technique which uses a cystoscope – a long, flexible, slender tube usually equipped with a camera, a light source, and some special instruments for biopsy or surgery. This enables to look inside the bladder by passing the cystoscope into the bladder via urethra to determine the presence and extent of the disease. Also, it helps in transuretheral resection of bladder tumor which is both, diagnostic as well as therapeutic.

As you can see in this figure, only cancer containing superficial layers of the bladder is removed, without damaging the deeper layers.

Transurethral resection of bladder tumor (TURBT)

If the abnormal area(s) are observed during cystoscopy, biopsy samples are collected from the abnormal area through a transurethral resection of bladder tumor (TURBT) or transurethral resection (TUR) technique. The tumor along with underlying muscle tissue is removed to check the extent of invasion into the bladder wall. Multiple biopsies may be obtained depending upon the cystoscopy observations. This technique helps in establishing the stage of the disease.

Intravenous Pyelogram

In this technique, various x-ray images are taken of the urinary system after injecting a contrast (dye) into patient’s vein. The dye outlines the complete urinary system on the x-ray images and is excreted in the urine by kidneys. This helps the doctor to examine the urinary tract for any abnormal areas.

In some cases, we may require a Retrograde Pyelogram in which a dye is injected into the ureter with the help of cystoscope, followed by a series of images.

CT Scan or MRI

Pyelogram may be complemented with other imaging modalities, like CT scan or MRI, which help in better delineating the urinary tract.

 

Also, CT scan or MRI of the abdomen and pelvis helps to understand the local extention of the tumor to other structures and the involvement of regional lymph nodes. It also helps to diagnose the metastatic involvement of other structures.

Bladder Cancer Staging

The bladder is an inflatable, hollow muscular organ situated in the pelvis. The main function of the bladder is to store urine until it is excreted from the body through the urethra. In a normal adult, it can hold up to 800 mL of urine.

The walls of urinary bladder consist of mainly three layers: mucosa (made up of transitional epithelium cells), lamina propria (made up of connective tissue), and muscularis propria (made up of 3 layers of smooth muscle fibers).

Staging for bladder cancer is called as TNM staging system. It helps in disease prognostication and choosing an appropriate treatment strategy.

Stage 0 Bladder Cancer

Stage 0 bladder cancer includes cases of TaN0M0 and TisN0M0. This means Tis or Ta disease (as discussed below) without the involvement of regional nodes or distant spread of tumor.

The figure below shows the epithelium, that is the innermost layer of the bladder wall.

And Ta is the papillary tumor which is limited to the epithelium. Non-invasive papillary carcinoma also known as the papillary urothelial neoplasm of low malignant potential (PUNLMP)

Stage 1 Bladder Cancer

Stage 1 bladder cancer includes cases with T1N0M0 disease, that it T1 disease (as discussed below) without involvement of regional nodes or distant spread.

The layer of the bladder wall outside the epithelium is called as lamina propria, as shown in the figure below.

And T2b when it infiltrates into the outer muscle layer.

Whereas in females, it may extend posteriorly to involve the uterus or vagina.

This figure shows the pelvic and iliac group of lymph nodes which are the regional lymph nodes for the bladder.

Depending upon the number and location of the lymph nodes involved, it can be N1, N2, or N3.

 

N1 – Involvement of one regional lymph node in true pelvis

 

N2 – Involvement of multiple regional lymph node in true pelvis

 

N3 – Involvement of common iliac lymph nodes

Stage 4a also includes cases with tumor spread to lymph nodes beyond common iliacs (non-regional), like retroperitoneal, aortocaval, mediastinal nodes, etc (M1a).

 

Bladder cancer metastasis to distant sites largely depends on the extent of local infiltration, i.e. whether it is non-muscle invasive or muscle invasive. The muscle invasive bladder cancer has a higher likelihood of spread, owing to increased chances of cancer cells entering into systemic circulation. It also depends on the histology of bladder cancer, whether it is transitional cell or of atypical histology. Usually, atypical histology has a higher chance of distant metastasis.

 

The most common sites of metastasis in decreasing order are lymph nodes, bone, lung, liver and peritoneum. The sites of metastasis is usually similar in different T stages, but in atypical histology tumors, peritoneal metastasis is more common than transitional cell histology.

 

Distant metastases from bladder cancer may occur to the bones. Or to the liver in the form of multiple nodular deposits.

 

It may also spread to one or both the lungs as seen in this figure.

 

Or to the peritoneum in form of multiple peritoneal deposits.

 

Based on the TNM staging discussed above, bladder cancer may be classified into 4 stages as mentioned below.

STAGE	TNM
0a	Ta N0 M0
0is	Tis N0 M0
I	T1 N0 M0
II	T2a N0 M0 T2b N0 M0
IIIa	T3 N0 M0 T4a N0 M0 T1-4a N1 M0
IIIb	T1-4a N2-3 M0
IVa	T4b Any N M0 Any T Any N M1a
IVb	Any T Any N M1b

 

Survival Rate/Life Expectancy based on Stage

It is calculated based on whether the disease is Localised, Regional or Dstant.

Localised disease

• Cancer is limited to the bladder.
• 5 year survival 70%.

Regional disease

• Cancer has spread to nearby structures or lymph nodes
• 5 year survival 36%.

Distant spread

• Cancer has spread to distant body parts like lungs, liver or bones.
• 5 year survival 5%.

Treatment for Bladder Cancer

Treatment of bladder cancer depends on the stage, type, unifocal/multifocal, performance status of the patient, along with other factors. But the final treatment decision is taken by the oncologist after clinical evaluation of the patient.

First step is to a cystoscopy. In this technique, a hollow tube called a cystoscope which is fitted with a camera is inserted into the urethra and is slowly advanced into the bladder. It helps to confirm the presence of a bladder tumor and see its location, number, and extent. Also, it helps in transurethral resection of bladder tumor which is both diagnostic and therapeutic.

 

 

As you can see in this figure, only cancer containing superficial layers are removed, without damaging the deeper layers.

 

This helps us to determine whether the bladder tumor is Non-Muscle invasive or Muscle invasive.

Stage 0 Bladder Cancer Treatment

This is carcinoma in situ which is a flat tumor, limited to the epithelium.

Intravesical chemotherapy should be given in all cases of This disease. As you can see in the figure, in this procedure the chemotherapy drug is directly instilled into the bladder, with the help of a catheter. Ta is the papillary tumor which is limited to the epithelium.

 

For Ta disease also, intravesical chemotherapy may be given. But in some cases, intravesical chemotherapy may not be required, when we can keep the patient under observation.

 

In intravesical therapy, drug is placed directly into the bladder using a catheter. It can produce local action without affecting other body parts. Drugs like mitomycin, valrubicin, docetaxel, thiotepa, and gemcitabine can be given by this technique. Bacillus Calmette-Guerin (BCG) (a modified tuberculosis bacterium) can also be given by this technique, which acts by activating the body’s immune system to destroy cancer cells. The most common side effects associated with intravesical therapy is irritation/burning in the bladder.

A bacterial vaccine– Bacillus Calmette-Guérin (BCG) (generally used to prevent occurrence of tuberculosis) is used in preventing early-stage bladder cancer recurrence. BCG stimulates the immune cells to attack bladder cancer cells.

It is generally employed as intravesical therapy after transurethral resection of bladder tumor (TURBT) or after surgical resection of some early-stage, high-grade, non-muscle invasive bladder cancers to prevent recurrence.

 

Induction intravesical BCG therapy is usually given once a week for 6 weeks. Two or more rounds of BCG induction therapy may be employed with a treatment-free interval of 4 to 6 weeks. Maintenance therapy with a monthly BCG dosing for about 1 to 3 years may be employed in some patients with high risk of disease recurrence.

Stage 1 Bladder Cancer Treatment

Stage 1 bladder cancer includes cases with T1 disease without any regional lymph nodes involvement or distant spread.

 

When the tumor infiltrates into the lamina propria, it is called as T1.

For T1 disease, the treatment depends on whether the tumor is low grade or high grade. Intravesical chemotherapy is the treatment of choice for low-grade tumors.

Whereas, in high-grade tumors, apart from intravesical BCG, repeat TURBT is strongly advised.

 

High risk cases of T1 disease includes those with multifocal lesions, lymphovascular invasion, those associated with carcinoma in situ or having a variant high risk histology (micropapillary, nested or plasmacytoid). It also includes cases that recur after intravesical BCG. In such cases high-risk cases, the preferred modality of treatment is cystectomy or surgical resection of the bladder.

Stage 2 Bladder Cancer Treatment

Stage 2 bladder cancer includes cases with T2 disease, without the involvement of regional lymph nodes or distant spread of the tumor.

When it infiltrates into the inner muscle layer, it is called as T2a. And T2b, when it infiltrates the outer muscle layer.

For T2 disease, radical cystectomy is advised. It involves cystoprostatectomy in  men that includes the removal of bladder, prostate, proximal part of urethra and vas deferens. Whereas, in women, it usually involves the removal of prostate and uterus, along with fallopian tubes, ovaries, part of vagina and urethra. Resection of pelvic lymph nodes is always done in radical cystectomy.

 

Partial cystectomy is an option in some selected cases, when bladder tumor is located such that it can be removed with adequate margins without removing the complete bladder, eg. tumor at the dome of bladder. Also, there should be no area of carcinoma-in-situ elsewhere in bladder.

 

Bladder preserving approach may be considered in selected cases depending on size, location, depth of bladder tumor, condition of the patient along with other factors. Treatment in such cases is done with concurrent chemoradiation.

 

Chemotherapy should be considered in cases of stage 2 disease. It should be preferably given before the surgery (neoadjuvant chemotherapy). If not given in the neoadjuvant setting, then should be given after the surgery (adjuvant chemotherapy).

Stage 3 Bladder Cancer Treatment

Stage 3 includes cases of T3N0M0, T4aN0M0, T1-4aN1-3M0.

Till T2, the tumor is limited to the bladder wall. But when the tumor infiltrates through the bladder wall to involve the perivesical tissue, it is called T3.

 

And in T4 disease, the tumor infiltrates through the bladder wall to involve the adjacent structures. It may extend downwards to infiltrate prostate gland in males, as you can see in this figure. Whereas in females, it may extend posteriorly to involve the uterus or vagina.

 

For T3 disease, and selected patients of T4 disease, as discussed above, with nodes negative, the preferred modality of treatment is cystectomy, with chemotherapy, which may be given before or after surgery.

 

But for non-cystectomy candidates, in which we are not planning surgery, a combination of chemotherapy and radiotherapy may be used.

 

The tumor may also extend anterolaterally, to involve pelvic or abdominal wall.

 

 

This figure shows the pelvic and iliac group of lymph nodes, which are the regional nodes for a bladder. Depending upon the number and location of the nodes involved, it can be N1, N2 or N3.

 

 

In selected patients of T4 disease, with abdominal or pelvic wall extension, and any patient with the node-positive disease, the preferred modality of treatment is chemotherapy, with or without radiation therapy. And further therapy maybe decided to depend upon the response to initial treatment.

Stage 4 Bladder Cancer Treatment

Now let’s come to the treatment for stage 4 or metastatic bladder tumor. Distant metastasis from bladder cancer may occur to the bones. Or to the liver in form of multiple nodular deposits.

 

 

  It may also spread to one or both the lungs as seen in the figure.

 

 

 

Or to the peritoneum in form of multiple peritoneal deposits.

 

 

Chemotherapy or immunotherapy is the mainstay of treatment for metastatic disease. But other modalities like surgery, radiation therapy, or bone-directed therapy may be used for palliation or relief of symptoms.

 

Chemotherapy drugs that are part of bladder cancer treatment regimens are-

• Gemcitabine
• Cisplatin
• Carboplatin
• Methotrexate
• Doxorubicin
• Vinblastine
• Paclitaxel
• Ifosfamide

 

Atezolizumab, an PD-L1 inhibitor, has been approved as the first-line therapy for patients with locally advanced or metastatic bladder cancer who are not eligible for any platinum-containing chemotherapy, regardless of the PD-L1 expression level.

 

Pembrolizumab, Atezolizumab, Nivolumab, Durvalumab, and Avelumab. These immune-checkpoint inhibitors have been approved as the second-line treatment of locally advanced or metastatic urothelial cell carcinoma (most common type of bladder cancer) that has progressed on or after platinum-based chemotherapy. These agents can be employed for the treatment of patients who have progressed within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. The PD-L1 expression levels estimation is not a pre-requisite for employing these agents as second-line treatment.

Always remember that metastatic disease is not generally curative. So the intent of the treatment is a prolongation of life, reduction of symptoms, and improvement in the quality of life of the patient.

Best Bladder Cancer Specialist in Delhi

Dr Sunny Garg is a renowned Medical Oncologist in New Delhi with an experience of around 10 years of treating bladder cancer patients. He has treated bladder cancer patients with Intravenous and  Intravesical Chemotherapy and Immunotherapy . He is currently practicing at Manipal Hospital, Dwarka.

Diagnostic modalities available at our hospital include Cystoscopic Biopsy, Transurethral Resection of Bladder Tumor, Intravenous Pyelogram, Urine Cytology, etc. Other treatment facilities for Bladder Cancer available are Radical Cystectomy, Partial Cystectomy, Radiation Therapy etc.

Call +91 9686813020 for appointment.