Patients

The urinary bladder collects urine produced by the kidneys and stores it until urination. It is a sac-like organ built of four layers:

• Urothelium is the inner layer
• Connective tissue is the next layer
• Muscle layer helps the bladder contract while urinating
• Fat layer surrounding the organ

Bladder cancer that starts with abnormal cell growth in the inner bladder layer and can progress towards the outer layers, is usually called urothelial carcinoma or transitional cell carcinoma. This is the most common bladder cancer [1].

Most bladder cancers are diagnosed as non-muscle-invasive bladder cancers (NMIBC). This means the tumors did not grow into the muscle layer of the bladder. NMIBC tumors can easily be treated by local resection, but up to 50% of patients will experience a recurrence of the disease.

• Smoking results in the accumulation of harmful chemicals in the urine. It is the most common risk factor [3, 4].
• Age as 90% of bladder cancer diagnoses are made in adults older than 55 years [4].
• Exposure to certain occupational and environmental chemicals used in the manufacturing of rubber, leather, paint dyes, printing materials and textiles, and arsenic in drinking water [3, 4].
• Gender as the disease is 4 times more common in men than in women [4].
• Chronic bladder inflammation due to urinary infections, kidney stones or bladder stones [5].
• Previous cancer treatment with cyclophosphamide or radiation [3].
• Personal or familial history of bladder cancer [3, 4].

With approximately 80% of patients attributable to known risk factors, prevention strategies such as smoking cessation, workplace safety practices and water disinfection are able to reduce the risk of bladder cancer [4].

Stage suggests the location of the tumor in relation to the inner lining of the bladder. The higher the stage the further the tumor has grown away from its original site on the surface. The following are the stages for bladder tumors: Ta: Papillary tumor without invading the bladder wall TIS (CIS): Carcinoma in situ (non-invasive flat high-grade(G3) cancer) T1: Tumor invades the connective tissue under the surface lining T2: Tumor invades the muscle layer T3: Tumor penetrates the bladder wall and invades the surrounding fat layer T4: Tumor invades other organs (i.e., prostate, uterus, vagina, pelvic wall) NMI-non muscle invasive (TO, Ta, Tis) 70-80% of newly diagnosed bladder cancer are Non-muscle invasive MI muscle invasive (T2, T3, T4)

• Painless hematuria (the presence of blood in the urine)
• Feel the need to urinate immediately
• Problems urinating
• Irritation while urinating
• Urinating more often than usual

These symptoms are, however, more often associated with a urinary tract infection than bladder cancer. Also other conditions can cause (some of) these symptoms. For instance, painless hematuria is often caused by kidney stones, blood thinners or other medications.

When experiencing red colored urine, although painless, temporary and infrequent, it is advisable to see your primary care physician.

Cytology and cystoscopy

 These two diagnostic approaches are considered the gold standard in the diagnosis of bladder cancer [1].

 Cytology is the examination of a urine sample under a microscope, which is performed in a laboratory to detect the presence of cancer or pre-cancer cells.

 During a cystoscopy, a thin tube with a camera is inserted through the urethra (the duct that that lets urine out of the bladder during urination) into the bladder. This procedure, performed at an outpatient clinic in the hospital or in the urologist’s office, enables the urologist to examine the inner layer of the bladder. Cytology is invasive and usually associated with discomfort or pain during or after the procedure.

When an abnormality is observed, a transurethral resection of bladder tumor (TURBT) is performed under general anesthesia in the operation room. The abnormal-looking tissue is removed and sent for microscopic investigation for the presence of cancerous cells.

Imaging

Imaging studies of the urinary tract are useful to investigate whether the cancer has spread outside the bladder into nearby tissues or lymph nodes. However, tumors in the bladder itself may be missed by imaging, so, bladder cystoscopy is always required for a proper diagnosis.

• CT urogram is a radiological exam in which a contrast dye is injected into the veins to outline the urinary tract. Multiple X-ray images are taken and sent to a computer to reconstruct detailed 2D images. This imaging technique can also identify kidney stones and swelling of the kidney due to downstream blockage.
• MR urogram uses a magnetic field and radio waves to produce detailed pictures. This technology does not use radiation or contrast dyes and it is useful to detect disease spread.
• Renal ultrasound applies sound waves for the shaping, sizing and localization of the kidneys. Although it is safe because it does not use radiation or a contrast dye, small kidney stones and tumors may be missed.

Grading and staging a bladder cancer tumor

Grade (ranging from 1 to 3): describes what the cancer cells look like and how many cells are multiplying. Grading is important to predict how fast the cancer will grow and spread. The higher the grade, the more the cells differ from normal bladder cells and the faster they spread.

Stage (ranging from 0 to 4): the extent to which the disease has progressed. Staging is used to plan the best treatment strategy for the cancer. The higher the stage the more the disease has grown into the layers of the bladder.

Three different parameters are often used in the staging system of bladder cancer: T, N and M:

• T categories describe how deep the tumor has grown into the bladder wall and if the tumor has invaded nearby tissues
• N categories describe whether the tumor has spread to lymph nodes
• M categories describe whether the tumor has spread to distant organs

The T categories define the bladder tumor itself:

• Ta: a papillary tumor with a long, thin finger-like structure growing in the inner urothelium layer
• CIS (carcinoma in situ), TIS: a superficial flat tumor on the inner layer
• T1: a tumor invaded in the connective tissue lining, but not into the muscle
• T2: a tumor invaded the muscle layer of the bladder wall
• T3: a tumor penetrated through the bladder wall and invaded the fat layer surrounding the bladder
• T4: a tumor invaded other nearby organs such as the uterus, prostate, vagina or pelvic wall

Ta, CIS and T1 are NMIBC and account for approximately 70-80% of all newly diagnosed bladder cancers, and T2, T3 and T4 are muscle invasive and more difficult to treat.

Cystoscopy combined with cytology is the currently recommended procedure. Follow-up procedures are usually scheduled every 3 months in the beginning and then twice-yearly and eventually annually. A cystoscopy at every follow-up visit is burdensome for the patient as the invasive procedure can cause discomfort and pain and needs to be performed in an outpatient clinic in the hospital, or in the urologist’s office.

Bladder EpiCheck® is a urine test to monitor tumor recurrence in NMIBC patients in conjunction with cystoscopy. Based on the results of a clinical study performed in leading medical centers in the Netherlands, Germany, Spain and Israel [7] a negative result rules out high-grade tumors with high certainty.

The urine sample is conveniently collected at the hospital, or at home:

• Read more about the Nucleix BE Safe @Home project, which aims to bring bladder cancer surveillance to the patient’s doorstep.

If you are a NMIBC patient, ask your urologist for more information on how the Bladder EpiCheck® test may improve your follow-up for tumor recurrence.