Bladder Cancer

What is Bladder Cancer?

Bladder cancer is a common type of cancer that occurs in the bladder, the hollow organ that holds your urine. The most common type of bladder cancer, called urothelial carcinoma, makes up over 90% of bladder cancer cases in developed countries. Bladder cancer is usually seen in older adults. Some of the things that can put you at risk for this type of cancer include smoking, being exposed to certain chemicals, and having long-lasting bladder inflammation. Symptoms that might signal bladder cancer include visible or microscopic blood in the urine, needing to urinate frequently, and feeling pain in the pelvic area. Catching bladder cancer early and starting treatment quickly can improve the chances of beating the disease. Bladder cancer can range from types that only affect the inside layer of the bladder to types that can spread deeper into the bladder and to other parts of the body.

The main way to treat bladder cancer is through a procedure called transurethral resection, which involves removing the cancer through the urethra, and instilling chemotherapy drugs directly into the bladder. Other treatment options include using a laser to remove the cancer, treating the bladder with a specific bacteria that can help fight the cancer (Bacillus Calmette-Guerin therapy), radiation therapy, chemotherapy, or surgery to remove part or all of the bladder.

This information covers everything from the causes of bladder cancer to the ways it’s treated. It talks about the latest developments and the best ways to diagnose, treat, and manage this common type of cancer. By understanding this information, you will be better able to recognize symptoms, know what treatment options are based on solid evidence, and keep up with the latest research. The goal is to deepen your understanding of bladder cancer and how it’s looked at in the medical world.

Working with a team of different healthcare professionals improves patient outcomes. This integrated approach ensures that you have a comprehensive treatment plan, and provides care that considers all aspects of your health. This leads to better overall management and prognosis of bladder cancer.

What Causes Bladder Cancer?

Urothelial carcinoma, a type of bladder cancer, develops in two ways. One way is associated with unusual growths called papillary neoplasms, and the other way relates to flat or sessile lesions, which are flat or slightly raised areas of abnormal tissue.

Non-muscle-invasive bladder cancers (NMIBC) are generally low-grade papillary tumors, which are occasionally caused by simple overgrowth of cells and/or minor abnormal cell growth. Included in this category is carcinoma in situ (CIS), a type of cancer that is aggressive but stays within the surface layer of cells.

Some characteristics of NMIBCs include:

* Mutations activating fibroblast growth factor receptor 3, a protein that helps with development and repairing tissue
* Inactivation of STAG2, another protein
* Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform, an enzyme
* The loss of a particular region on chromosome 9
* Telomerase reverse transcriptase, an enzyme that helps protect the ends of chromosomes

About 10% of the low-grade papillary NMIBC cases can turn into a cancer that invades the muscle layers due to the loss of cyclin-dependent kinase inhibitor 2A, a protein that helps control cell growth.

On the other hand, muscle-invasive bladder cancer (MIBC) results from flat abnormal cell growth or carcinoma in situ. This type is marked by:

* Mutations in the TP53 gene and loss of a region on chromosome 9
* Invasive carcinoma, a type of cancer that can spread to other parts of the body, can gain this ability through the loss of RB1 and PTEN, along with other alterations
* Changes in the number of copies of a gene and genetic instability, which are associated with cancer progression and a worse outlook
* NMIBC typically has normal or near-normal chromosome numbers, compared to muscle-invading types
* MIBC usually has abnormal chromosome numbers and many changes in the chromosomes

Recent research has discovered four types of NMIBC based on abnormal ribonucleic acid (RNA) expressions. These unusual prognostic molecular types involve early cell cycle abnormalities, chromosomal instability, stem cell-like disorders, and immune depletion problems. The most significant of these seems to be chromosomal instability, as it has the highest recurrence and progression rates.

Risk Factors

Bladder cancer has many known risk factors. Significant ones include smoking, schistosomiasis infection, a disease caused by Schistosoma parasites, and work exposure to specific chemicals. Smoking is noted as the most crucial known risk factor as the average risk in smokers is three times more than in non-smokers; the risk depends on how long and how much people have smoked. At least 50% of people found with bladder cancers will be current or ex-smokers. People who smoke also tend to develop more aggressive tumors and have a worse outlook. Quitting smoking lowers the bladder cancer risk, which eventually nears that of nonsmokers. Within the first four years after quitting smoking, the chance of getting bladder cancer drops by 40% and is reduced by 60% after 25 years.

In developing countries, an infection due to schistosomiasis is a significant cause of bladder cancer. Schistosoma haematobium ova, eggs of the Schistosoma haematobium parasite, can get stuck in the bladder wall, causing irritation and inflammation. This can ultimately lead to cancer of the urinary bladder’s squamous cells, a flat type of cell found in the skin and some internal organs. It’s estimated that about 600 million people are at risk in endemic areas of Africa, Asia, the Caribbean, and South America.

Genetic and/or environmental factors also impact the risk of developing bladder cancer, but only account for about 7% of all such cases. Chemicals linked to bladder cancer include arylamine and aniline dyes, formaldehyde, phenacetin, cyclophosphamide, and arsenic in drinking water.

Work exposure to paint, rubber, petroleum products, agricultural chemicals, and dyes heightens the risk of bladder cancer. Jobs that typically have the most exposure to such chemicals encompass:

* Workers in agriculture
* Barbers
* Bartenders and waiters
* Beauticians
* Employees in chemical plants
* Workers in dental offices
* Dry cleaners
* Housecleaners
* Metalworkers (welding)
* Workers in oil refineries
* Painters
* Workers in paper production
* Workers producing or using pesticides
* Workers producing rope, string, and twine

Risk Factors and Frequency for Bladder Cancer

Bladder cancer is one of the most common cancers in the United States, ranking fourth in men, eighth in women, and fifth overall. It’s more common in men than women, with a ratio of 4:1. Although women are diagnosed less frequently, they often have a more advanced stage of the disease, and it tends to be more severe. In 2023 alone, there were 82,290 new cases and 16,710 deaths from bladder cancer. Making up 4.2% of all new cancer diagnoses and 2.7% of all cancer-related deaths, the overall survival rate over five years is 77.9%. Thankfully, the number of new cases and deaths is slowly decreasing by about 1% each year.

Bladder cancer is twice as common in White populations as Black populations, with increasing risk as people age, especially those over 70 years old. Despite this, Black individuals statistically have a lower survival rate than other groups. In the US, the most common type of bladder cancer is urothelial, but globally, 75% of cases are squamous cell carcinomas, which is closely linked to a disease called schistosomiasis.

Globally, bladder cancer is ranked as the seventh most common cancer. The yearly rate is 9.5 per 100,000 men and 2.4 per 100,000 women. In 2020, bladder cancer resulted in the deaths of 213,000 people worldwide. Interestingly, bladder cancer is twice as prevalent in developing countries compared to highly industrialized ones. As per the World Health Institute (WHO), Greece has the highest overall risk of bladder cancer, followed by the Netherlands, Italy, Denmark, Belgium, and Spain. The highest death rate from bladder cancer is reported in Egypt, then Tunisia, Libya, Poland, and Mali.

Signs and Symptoms of Bladder Cancer

Bladder cancer is a disease that mainly affects adults aged 60 and above. It often starts with the presence of blood in the urine, either visible to the eye or only under a microscope. This is the first symptom for many patients. In fact, more than one third of patients with visible blood in the urine, and slightly over 10% with microscopic blood in the urine, will eventually be diagnosed with bladder cancer. Less common symptoms can include painful urination, need to urinate more frequently, a lump in the pelvic area, or general symptoms like fatigue and weight loss.

Doctors recommend a thorough health history and physical exam for any patient with unexplained blood in the urine. This helps identify any risk factors for bladder cancer or other sources of bleeding, such as kidney disease, kidney tumors, bladder stones, reproductive issues in women, enlarged prostate, and other non-cancerous urinary conditions. For women, this examination should also include an examination of their pelvic area and external genitalia. Patients taking blood thinners would undergo the same evaluation.

If the cause of the blood in the urine isn’t cancer, patients should have follow-up urine tests after treatment to make sure the issue has resolved. If there’s still blood in the urine, further evaluation may be needed. As an example, if a urinary tract infection caused microscopic blood in the urine, a follow-up microscopic urinalysis could help confirm that the infection and the blood in the urine have resolved.

There are no specific screening tests for early bladder cancer detection, other than identifying unexplained, ongoing blood in the urine. Visible blood in the urine could indicate more advanced bladder cancer. Risk factors include a history of smoking, with a history of 10 pack-years (smoking an average of one pack of cigarettes per day for a year) or more significantly increasing the risk of bladder cancer. Blood in the urine in patients with protein in the urine, unusually-shaped red blood cells, cellular residue in the urine, or kidney failure might suggest kidney disease as the source.

Several high-risk factors for bladder cancer can be identified, including:

• Having a chronic urinary catheter or foreign body
• Undergoing chemotherapy, specifically with cyclophosphamide or ifosfamide
• Having symptoms of urinary irritation
• Previous exposure to pelvic radiation
• Being older
• Being male
• Having a family history of bladder cancer, or Lynch syndrome, Peutz-Jeghers syndrome, or Cowden syndrome
• Smoking a pack a day for 10 years or more
• Exposure to toxic chemicals, such as aromatic amines and hydrocarbons, arsenic, products containing benzene, formaldehyde, nitrosamine, petrochemicals, or rubber

Additionally, infection with the parasite Schistosoma hematobium increases the risk of a certain type of bladder cancer, squamous cell carcinoma, especially in parts of the world where the parasite is common.

Testing for Bladder Cancer

Screening specifically for bladder cancer is typically not done. If routine urine tests detect blood in your urine, known as hematuria, your doctor may then evaluate you for a possible bladder cancer diagnosis. Methods used for detection include imaging tests like ultrasound, CT scan, and MRI, tests to bone or look inside the bladder (cystoscopy), tests for cancer cells in the urine (cytology), and direct sampling or removal of tissue (biopsy). Intravenous pyelography, a test that was formerly used, is not in use anymore.

The American Urological Association provides a risk guide to help categorize patients:

Low-risk patients typically have trace amounts of blood in their urine and meet specific criteria, such as being a non-smoker or younger than a certain age. These patients can proceed with an ultrasound and cystoscopy or get another urine test six months later.

Intermediate-risk patients have a bit more blood in their urine or meet one or more high-risk factors. For them, an ultrasound and cystoscopy are recommended.

High-risk patients are either older, have a history of heavy smoking, or have more blood cells in their urine. They should be studied with a specific type of CT scan and a cystoscopy.

To get a detailed look at the bladder, doctors rely on imaging tests. For low-risk patients, an ultrasound may be used, but it might miss small tumors. High-risk patients or those who are not low or intermediate risk often require a CT scan. This scan is also needed if a bladder tumor is confirmed through another test.

When you get a CT scan, it is usually done in three stages, each focusing on a different aspect of urinary architecture and potential abnormalities. This approach allows for superior detection and visualization of bladder issues, with an accuracy of over 90%.

If a contrast dye cannot be used, an MRI can be performed instead. MRI is also better for staging aggressive cancers with a reported accuracy of over 90%. Other imaging techniques are being developed that may predict the invasion and grade of the tumor even better.

For certain patients, the 18F-fluoro-deoxy-glucose positron emission tomography (FDG-PET) test can be beneficial for staging before a significant surgery, but its role is still being fine-tuned.

When managing bladder cancer, cystoscopy is the ‘gold standard.’ It’s reported to be highly sensitive, meaning it accurately identifies those with the disease. But because its sensitivity may vary, it might need to be repeated or complemented by other techniques, especially in high-risk or uncertain cases. This procedure is usually done with minimal anesthesia.

Bladder cancer can take different forms and appear differently when visualized. Non-muscle-invasive cancer usually appears as one or more papillary projections, while muscle-invasive cancer may appear as a flat tumor or another form. The precise identification and evaluation of these forms require the removal and sampling of the tissue.

Cancerous tissues may look very similar to routine inflammation, making them hard to detect. To enhance detection, a technique that uses ‘blue light’ during the examination may be used. This method shines a particular light that causes cancer cells to ‘glow,’ allowing the doctor to see and remove them.

There are other tools doctors use to check on bladder cancer or monitor its progression, like cytology tests (examining cells under a microscope) and FISH tests (detecting abnormal changes in cells), but they have limitations and are reserved for certain situations.

The use of urinary markers or genes in urine tests is also being explored for monitoring and detecting bladder cancer. Within the cystoscopy, there are techniques that enhance the detail and visibility of unusual tissues, like narrow-band imaging. The role and usage of these advancements are still being defined.

Treatment Options for Bladder Cancer

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What else can Bladder Cancer be?

When diagnosing bladder cancer, doctors look at numerous possible causes because the symptoms are similar to those of other urinary and body-wide conditions. The potential causes for bladder cancer symptoms include:

• Amyloidosis
• Enlarged prostate (Benign prostatic hyperplasia)
• Thickening of bladder wall due to a blockage or infection
• Cystitis cystica and glandularis (Inflammation of the bladder)
• Diverticulitis (inflammation of the bowel)
• Enterovesical fistula (an abnormal connection between the bladder and intestines)
• Gynecological and other pelvic cancers
• Hemangioma (abnormal buildup of blood vessels in the skin or internal organs)
• Blood in the urine not related to bladder cancer (Hematuria unrelated to urothelial carcinoma)
• Bleeding inflammation of the bladder (Hemorrhagic cystitis)
• Inverted papilloma (a non-cancerous tumor)
• Interstitial cystitis (painful bladder syndrome)
• Leiomyoma (a benign tumor in smooth muscle tissue)
• Malakoplakia (a rare inflammatory condition that affects various parts of the body)
• Median lobe of the prostate with intrusion into the bladder
• Nephrogenic adenoma (benign tumor of the kidney or urinary tract)
• Kidney stones (Nephrolithiasis)
• Overactive bladder
• Paraganglioma (a rare growth that usually starts in specialized cells along nerve pathways)
• Prostatitis (swelling and inflammation of the prostate gland)
• Radiation cystitis (bladder inflammation caused by radiation therapy)
• Renal masses and neoplasms (tumors or growths in the kidney)
• Urinary tract infection

In order to ensure correct treatment, it’s important to identify the precise cause of the symptoms.

What to expect with Bladder Cancer

The chances of survival for a patient with urothelial bladder cancer depends on many factors. The most crucial of these is the TNM stage – simply put, this classification provides information on the tumor size and extent (T), whether cancer has spread to the lymph nodes (N), and the presence of distant metastasis or spread of cancer to other body parts (M).

In terms of 5-year overall survival rates based on the TNM stage, we see the following: 75% for stage pT1, 50% for stage pT2, and 20% for stage pT3. Whether the cancer has spread into the muscle layer of the bladder wall (muscularis propria) helps doctors determine if the patient is at stage pT1 (NMIBC – non-muscle invasive bladder cancer) or pT2 (MIBC – muscle invasive bladder cancer).

Certain histological variants of urothelial carcinomas – basically, different forms of bladder cancer seen under a microscope – have a worse survival rate than typical bladder cancer. These forms include cancers with features of muscle-like cells (rhabdoid), small, multiple, finger-like projects (micropapillary), plasma cell-like (plasmacytoid), mix of sarcoma and carcinoma (sarcomatoid), small cell type, and ones that are so abnormal they can’t be classified (undifferentiated carcinoma).

Other factors making the outlook worse are high grade of the cancer cells, invasion of cancer into lymph or blood vessels, presence of carcinoma in situ (CIS, a type of non-invasive cancer), recurrence of cancer, large tumor size, tumor attached to the surface of an organ (sessile), incomplete removal of the tumor, cancer at the edge of the removed tissue (positive margins), and cancer presence in multiple areas (multicentricity).

According to the National Cancer Institute, the 5-year survival rates for bladder cancer are as follows;

– CIS: 97%. However, about half become invasive within 5 years, and just over half will show tumor worsening unless treated with medication like BCG, in which case the risk drops to less than 10%.
– Localized bladder cancer: 71%.
– Regional bladder cancer (spread to nearby organs or lymph nodes): 39%.
– Metastatic bladder cancer (spread to distant body parts): 8%.

Possible Complications When Diagnosed with Bladder Cancer

Bladder cancer complications can come in two forms: those related to the tumor itself, and those that occur as a result of the treatment. Complications from the tumor can cause weight loss, tiredness, urinary tract infections, the tumor spreading to other parts of the body (metastasis), and urinary blockage leading to long-term kidney failure.

The surgical treatment of bladder cancer can also have adverse effects including urinary infections, leakage of urine, stones forming in the urinary pouch, blockage of the urinary tract, problems with erections, and narrowing of the vagina. Studies show that nearly two-thirds of patients who undergo bladder removal surgery (radical cystectomy) experience a problem within the first three months after the operation, with 13% suffering a severe complication.

A surgical bladder replacement, known as neobladder, can have its own complications, which include trouble with urinating, narrowing of the tube that carries urine from the kidney to the bladder (ureteroenteric strictures), urinary infections, bladder stones, metabolic abnormalities, urinary retention, and rupture. Among these, rupture or leakage of the neobladder can be particularly dangerous, especially for patients who experience abdominal pain after the bladder replacement surgery. This is usually diagnosed with a CT cystogram and traditionally treated with a surgical repair, but in select early and stable cases can be treated conservatively. Continued leakage or lack of improvement should be managed surgically.

Lastly, besides complications related to general anesthesia and surgical procedures, there is a considerable list of potential complications, outlined as below:

• Bleeding and Vascular Issues: Anemia, blood clotting disorders, deep vein thrombosis, hematoma formation, inflammation of veins, blood in urine for prolonged period, lung clots, and need for blood transfusion
• Gastrointestinal Problems: Bowel leaks, fluid in the abdomen, diarrhea, vomiting, abnormal connections between the bowel and skin, bleeding in the stomach, slowed down or stopped bowel function, peptic ulcers, inflammation of the colon, and small bowel obstruction
• Genitourinary Issues: Bladder dysfunction or perforation, strictures of the bladder neck, erectile dysfunction, abnormal connections between organs (fistulas), swollen part of the ureter, hernias near the stoma, kidney failure, problems with the stoma, ureteral or urethral strictures, problems with urination including urinary retention and incontinence
• Infections: Abscesses, cellulitis, inflammation of the gallbladder, inflammation of the diverticulum, wound infections, infection in the abdomen, kidney infection, sepsis, and unexplained fevers
• Surgical Complications: Bladder perforation, cellulitis, failure to identify bladder cancer, fistula formation, nerve injury, incomplete tumor resection, hernia at the incision site, unrecognised injury to intestines, parastomal hernia, injury to rectum, left over drain, seromas, stoma necrosis, vascular injury, and problems with wound including wound infections.

Recovery from Bladder Cancer

If you have a history of Non-Muscle Invasive Bladder Cancer (NMIBC) and a recent examination of your bladder (cystoscopy) has shown no signs of cancer, but other tests (cytology) indicate potential issues, then your doctor may suspect that the disease has returned, or is hidden somewhere else in the body. In such cases, your doctor may suggest additional investigations, like imaging of the upper urinary tract, biopsy of the bladder, and advanced cystoscopy procedures using blue light or narrow band imaging.

The risk of NMIBC returning is categorized by the American Urological Association (AUA) into low, intermediate and high risks, based on various factors including the size, location, grade of the initial tumor, and how often it recurs.

The doctor will recommend follow-up cystoscopies after surgical treatment based on the risk levels. With low-risk cancers, the first follow-up may be three to four months after surgery. If all is clear, the next examination can be six-to-nine months later, followed by yearly check-ups for at least five years. Deciding whether to continue yearly checking after five years without a recurrence will depend on a discussion with you, the patient. In the case of low-risk cancers, additional tests and imaging are usually not necessary.

Intermediate-risk cancers will need cystoscopy checks with cytology every three to six months for two years. After two years, checkups should be moved to every six to twelve months for another two years and then yearly. At this risk level, doctors may suggest imaging of the upper urinary tract every one to two years.

High-risk cancers will require the same follow-up schedule as intermediate-risk ones for the first four years. After these, the tests will be carried out annually. Some doctors may recommend bladder washing for cytology, particularly if there’s a history of high-grade cancer or Carcinoma in situ (CIS), a form of cancer that remains within the cells where it started. With high-risk patients, imaging of the upper urinary tract should also be considered every one to two years.

If you’ve had a cystectomy, or bladder removal, for Muscle Invasive Bladder Cancer (MIBC), the AUA recommends that for the first two-to-three years, regular image check-ups of the chest along with MRI or CT scans of abdomen and pelvis should be performed at six-to-twelve-month intervals. If the urethra wasn’t removed during surgery, it should be regularly examined for possible recurrences. This can be accomplished using cytology examinations of urethral washings.

Furthermore, if you’ve undergone bladder Preservation Therapy, your doctor will advise regular check-ups every three months for the first year using cystoscopy and cytology. After the first year, these reviews should be done every four to six months for another year, then every six to twelve months. Imaging of the chest, and MRI or CT scans of the abdomen and pelvis, should be performed at six-month intervals for two years.

Preventing Bladder Cancer

Preventing and managing bladder cancer requires alertness and patient education. Patients should learn about how to reduce risk factors such as stopping smoking and limiting exposure to industrial chemicals, as these steps can significantly lower their overall risk. Organizations like the American Cancer Society and SmokeFree.gov can help patients stop smoking. Healthcare professionals need to highlight the importance of recognizing early signs, such as seeing blood in the urine, and seeking prompt medical attention. Patients should also be aware that symptoms such as painless blood in urine, symptoms of a urinary tract infection that aren’t caused by an infection and don’t respond to antibiotics, or symptoms of bladder irritation may be early signs of bladder cancer of the urothelial type.

For those who have a history of bladder cancer, regular follow-up checks and monitoring are very important due to the high chance that the cancer may return. Patients diagnosed with a non-muscle invasive form of bladder cancer (NMIBC) should be given a clear schedule to follow for their bladder check-ups and should strongly consider quitting smoking if they haven’t already. The National Comprehensive Cancer Network provides a free guideline for bladder cancer patients on their website NCCN.org/patientguidelines. Moreover, talking about lifestyle changes, such as keeping a good diet and staying hydrated is very beneficial for the overall health of the urinary tract. The more knowledge patients have, the better they can take positive steps towards their health and improve their quality of life.