- Overview on Bladder Cancer
Bladder is a layer structure organ storing a urine. The following tissue layers form the bladder wall:
- Inner layer (called lining) – built from transitional cells stretching when the bladder is filled by urine
- Middle layer – muscle tissue responsible for removing the urine outside the body
- Outer layer – covers urine and is comprised of fat tissue and blood vessels.
Cancer of the urinary bladder is caused by abnormal cell growth leading to forming a mass of tissue (tumour) in bladder lining. Depending on the origin of cancerous cells, three types of bladder cancer can be distinguished. The most common cancer type begins in the innermost part of the bladder from transitional cells (urothelial cell carcinoma, 90% of cases). The remaining cases includes squamous cell carcinoma (begins in flat and thin squamous cells) and adenocarcinoma of the bladder (begins in cells producing mucus) (Figure 1).
Depending on the level of infiltration of the cancerous cells through layers of bladder wall, non-muscle invasive (limited to innermost layer), muscle invasive (growing beyond muscle layer) and metastatic cancer (spreading out the bladder to other organs and lymph nodes) can be discriminated (Figure 1).
The majority of the initially diagnosed bladder cancer cases are detected at the non-invasive stage (70%). However, along with the advancement of the tumour, patients have a poorer prognosis and limited treatment options. Therefore, early detection is of paramount importance to improve disease outcome.
Bladder cancer exhibit high recurrence (80%) and progression rates (10-15%) mandating the life-long monitoring of patients after treatment. The probabilities of recurrence and progression are calculated based on EORTC tables taking into account several factors such as a) number of tumours, b) tumour size, c) presence of recurrence, d) stage and e) grade. According to these factors patients can exhibit low/ intermediate or high risk of recurrence/ progression and these factors also has an impact on adjustment of aggressiveness of therapeutic strategies.
- Causes underlying development of bladder cancer
Various factors (called risk factors) might make a person more susceptible for developing bladder cancer including (Figure 2):
- Cigarette smoking – considered as a main risk factor for bladder cancer. Cigarette smoking is associated with half of bladder cancer cases.
- Working environment - Exposure at workplace to carcinogenic chemicals such as aromatic hydrocarbons, aromatic amines and chlorinated hydrocarbons, especially in the various parts of industry (i.e. production of dyes, rubber, textile, leather or chemicals)
- Age, Gender – Risk of developing bladder cancer increase with age and bladder cancer is more frequently detected in men than in women, with men to women incidence ratio at around 3:1
- Medical history of the patients including presence of urinary tract infections, schistosomiasis, previous treatment (radiotherapy, chemotherapy)
- Symptoms of Bladder Cancer
Hematuria (presence of blood in urine) is a first sign of early stage bladder cancer. As tumour advances, other symptoms may appear including increase frequency and painful urination or unexpected need to urinate. In the case of the infiltration of the tumour into muscle layer, pelvic and bone pain, loss of weight, inability to urinate or swelling of feet may occur. However, most of these symptoms are not specific for bladder cancer and might be attributed to presence of an infection or other disease.
- State of the art diagnostic and monitoring modalities
Up to date voided urine cytology and cystoscopy are considered as a golden standard for diagnosis and follow up of patients with bladder cancer.
Voided urinary cytology – non-invasive examination of urine to look for presence of cancer cells in urine.
Cystoscopy – invasive procedure used to examine the inside of the bladder by using cystoscope (thin tube with camera and light). The cystoscope is inserted through the urethra and may require an anaesthesia. The sample of the abnormal tissue can be also remove (biopsy) and further evaluated under a microscope by pathologist to assess the malignancy of disease.
Performance of the assay
The performance of the assay may be assessed by estimation of the sensitivity and specificity of the test. Sensitivity is applied to evaluate the proportion of patients correctly identified as “diseased”; whereas specificity is related to those healthy individuals, correctly identified with no presence of disease. According to the meta-analysis (compilation of results from independent studies) conducted by Mowatt, the overall sensitivity and specificity of cytology was 44% (38-51%) and 96% (94- 98%), respectively. In the case of white light cystoscopy, sensitivity of 71% (49- 93%) and specificity of 72% (47-96%) were reported.
- Staging and Grading
Stage of the cancer provides an information how deep the tumour has spread through bladder wall. Currently, the most commonly used method to assess stage is TNM classification system. This system informs how deep the tumour infiltrate the bladder wall (T), whether the cancer invade the lymph nodes (N) or other organs in the body (M).
Particularly, in the case of bladder cancer the following stages can be discriminated:
- CIS(carcinoma in situ) – high grade, detected at the innermost layer of the bladder
- Ta– the cancer is restricted to the innermost layer of bladder lining
- T1– the cancer starts spreading to the connective tissue under the lining
- T2 – the cancer invades the muscle tissue
- T3– the cancer has spread beyond the muscle tissue into fat layer
- T4– the cancer has grown outside the bladder
Grade of the tumour informs how the cancer cells differs from normal cells. Based on that pathologies may attempt to likely predict how fast the tumour will grow. The primary grading system developed in 1973, distinguish between three tumour grades including well (grade 1), moderately (grade 2) and poorly (grade 3) differentiated tumour.
According to the new grading system introduced in 2004 by World Health Organisation, for the non-muscle invasive urothelial neoplasia the following grades are distinguished:
- Flat lesions
- Hyperplasia (flat lesion without atypia or papillary)
- Reactive atypia (flat lesion with atypia)
- Atypia of unknown significance
- Urothelial dysplasia
- Urothelial carcinoma in situ (CIS)
- Papillary lesions
- Urothelial papilloma (a completely benign lesion)
- Papillary urothelial neoplasm of low malignant potential (PUNLMP)
- Low-grade papillary urothelial carcinoma
- High-grade papillary urothelial carcinoma
- Treatment options
Treatment strategies vastly differ for non-muscle invasive and muscle invasive bladder cancer, as the latter has a high risk for distant metastases. In general, therapeutic options applied for patients suffering from bladder cancer includes surgery (transurethral resection of bladder tumour, partial or radical cystectomy), biological therapy using BCG solution (Bacillus Calmette-Guerin), chemotherapy or radiotherapy. In addition, the combination of different strategies can be also used.
Standard treatment for NMIBC is the transurethral resection of the tumour (TURB, tumour is resected from bladder lining during cystoscopy by using a wire loop and the electric current is applied to burn remaining cancerous cells) followed by intravesical instillations of chemotherapy or Bacillus Calmette Guerin (BCG), while for MIBC a cystectomy is performed. Cystectomy is an open surgery applicable to remove part (partial cystectomy) or the entire bladder (radical cystectomy) along with the nearby lymph nodes. Also in the latter case, the part of the urethra is usually resected. However, with a 10-year disease-specific survival rate of 37%, the prognosis of patients undergoing RC, particularly those with advanced tumours (pT4 pN0), is unfavourably low. Thus, the European Association of Urology (EAU) suggests the use of neo-adjuvant chemotherapy in patients with advanced BC (pT2-T4a) in their most recent guidelines.
- Chemotherapy – therapeutic strategy utilizing drugs to fight with cancer. The drug can be administrated directly into the bladder, by mouth or into vein (intravenous). The latter method, is usually applied for muscle-invasive or metastatic cancer. The side’s effect of these therapy depends on the type and dose of the drug. This is mostly attributed to the fact that the drug may affect not only cancer cells, but also normal cells, especially these dividing rapidly (e.g. blood cells, cells in hair roots or in digestive system).
- Radiotherapy – Radiotherapy utilize the radiation with high energy rays to kill cancerous cells.
- Bacillus Calmet Guerin (BCG) – Biological treatment by using the solution containing weakened bacteria. In this way, the immune response is initiated and help to kill cancer cells
- BioMedBC Project
Bladder cancer is considered as 5th in incidence and 9th in mortality among all malignancies in Europe. Based on the GLOBCON analysis, the estimated number of newly diagnosed cases and BC related deaths in 2012 were 429,000 and 165,000, respectively. Limited treatment options as well as invasive nature of the procedure used for life-long monitoring of the patients remains the space for further improvements.
The pivotal objective of the project is a discovery of novel drug targets through broadening the knowledge about mechanism underlying bladder cancer invasion. Additionally, the program aims towards the improvement of the current status of Bladder Cancer management in a multilevel direction including the development of the non-invasive method to diagnose primary and recurrent tumour. Toward that end, three individual research projects have been started focusing on:
- Investigation of the value and relevance of already reported biomarkers for Bladder Cancer;
- Elucidation of molecular mechanisms, underlying bladder cancer invasion to identify the putative therapeutic targets;
- Consolidation of existing information from literature and publicly available databases with the newly collected –omics data in order to build the model of bladder cancer
Babjuk, M. et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2013. Eur Urol 64, 639-53 (2013).
Ferlay, J. et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer (2014).
Sylvester, R.J. et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 49, 466-5; discussion 475-7 (2006).
van Rhijn, B.W. et al. Recurrence and progression of disease in non-muscle-invasive bladder cancer: from epidemiology to treatment strategy. Eur Urol 56, 430-42 (2009).
Witjes, J.A. et al. EAU guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2013 guidelines. Eur Urol 65, 778-92 (2014).
BioMedBC is a Marie Sklodowska Curie Actions (MSCA) Individual Fellowship programme (H2020-MSCA-IF-2016)
funded by the European Union under the Horizon2020 Framework Programme (Grant Agreement:752755) and
coordinated by Mosaiques diagnostics