Several components found naturally in the environment and secondary to industrial waste have been associated with carcinoma of the bladder. Arsenic is a ubiquitous element that is widely distributed in nature and is transported in the environment mainly by water. Inorganic arsenic has significant association between arsenic exposure and subsequent risk of urinary tract cancer has been reported in epidemiologic studies carried out in an arseniasis-endemic area in south-western Taiwan as well as other countries with high levels of arsenic in drinking water (Chiou et al., 2001). The data on exposure to nitrate in drinking water is limited. A cohort study of 21,977 Iowa women found a positive association between nitrate in drinking water and UBC (Weyer et al., 2001). In contrast, two case-control studies did not observe a significant effect (Ward et al., 2001).
Chronic low-dose radiation could affect bladder urothelium through oxidative stress and impairment of DNA repair. Therapeutic pelvic radiation, used for dysfunctional uterine bleeding, ovarian, cervical and prostate cancer, is associated with an increase in UBC risk (Brenner et al., 2000).
5-Hereditary factors
Familial history of bladder cancer
Familial clustering of UBC has been described in several case-reports. Goldgar et al. (1994) reported an increased risk of lymphatic leukemia and cervical cancer probands. The largest population case-control study of 2,982 bladder cancer patients and 5,782 controls conducted in USA found a risk of 1.45 for those with a first-degree relative with cancer of the genitourinary tract (Kanter et al., 1985).
Pathologic staging of bladder cancer
Cancers are divided into stages, depending on how far they have grown. The staging system normally used in bladder cancer is called TNM, which stands for ‘tumor, node, and metastases. So TNM staging takes into account how deeply the tumor has grown into the bladder, whether there is cancer in the lymph nodes, and whether cancer has spread to other parts of the body (metastasis) (Droller, 2006). The main features of each stage of the disease are:
‘ Stage 0- The cancer cells are found only on the surface of the inner lining of the bladder. It is called superficial cancer or carcinoma in situ.
‘ Stage I -The cancer cells are found deep in the inner lining of the bladder. They have not spread to the muscle of the bladder.
‘ Stage II – The cancer cells have spread to the muscle of the bladder.
‘ Stage III – The cancer cells have spread through the muscular wall of the bladder to the layer of tissue surrounding the bladder. The cancer cells may have spread to the prostate (in men) or to the uterus or vagina (in women).
‘ Stage IV – The cancer extends to the wall of the abdomen or to the wall of the pelvis. The cancer cells may have spread to lymph nodes and other parts of the body far away from the bladder, such as the lungs.
Grading of bladder cancer
Grading of tumors by the pathological examination, after the tumor has undergone biopsy and resection, provides information about the potential behavior of the tumor (Kirkali et al., 2005). Low grade (Grade 1) tumors look more like normal bladder cells, and tend to remain on the surface of the bladder lining, while the high grade (Grade 3) tumors have much angrier looking cells and tend to shed cells into the urine, and are more likely to invade into the bladder surface.
‘ Grade 1 cancers have cells that look very like normal cells – they are called 'low grade' or 'well differentiated' and tend to grow slowly and are not likely to spread
‘ Grade 2 cancers have cells that look more abnormal – they are called 'medium grade' or 'moderately differentiated' and may grow or spread more quickly than low grade
‘ Grade 3 cancers have cells that look very abnormal – they are called 'high grade' or 'poorly differentiated' and are more quickly growing and more likely to spread
Cheng et al., 2012 developed a new grading system for early bladder cancer, which is increasingly being used. This system divides bladder cancers into urothelial papilloma (non cancerous benign tumor) and papillary urothelial neoplasm of low malignant potential (PUNLMP)-slow growing and unlikely to spread
Free radicals
Oxidative stress caused by increased free radical generation and/or decreased antioxidant level in the target cells and tissues has been suggested to play an important role in carcinogenesis (Rajneesh et al., 2008). Free radicals are capable of altering all major classes of biomolecules, such as lipids, nucleic acids and proteins, with changes in their structure and function (Guyton and Kensler, 1993).
They are a chemical species that possess an unpaired electron in the outer (valence) shell of the molecule. This is the key factor in the structure of this species (Greenwald, 1991; Halliwell, 1995) and is the reason why they are highly reactive. These species are in reality composed of a group of molecular fragments that are capable of independent existence (Cheeseman and Slater, 1993).
The fact that they are highly reactive means that they have low chemical specificity; i.e. they can react with most molecules in its vicinity. This includes proteins, lipids, carbohydrates and DNA. It also means that in trying to gain stability by capturing the needed electron they don't survive in their original state for very long and quickly react with their surroundings (Cheeseman and Slater, 1993). Hence, free radicals attack the nearest stable molecule, "stealing" its electron. When the "attacked" molecule loses its electron, it becomes a free radical itself, beginning a chain reaction. Once the process is started, it can cascade, finally resulting in the disruption of a living cell (Cheeseman and Slater, 1993).
Free radicals are produced continuously in cells either as by-products of metabolism or deliberately as in phagocytosis (Cheeseman and Slater, 1993). These radicals have both beneficial and harmful actions in biological tissues. They are known to have a crucial role in stimulation of phagocytosis, induction of drug detoxification pathways and stimulation of signal ‘transduction pathways (Salganik, 2001; Droge, 2002). However, these same radicals can be potentially dangerous products of cellular metabolism in that they can directly influence cell growth and development, cell survival and likely increase the pathogenesis of atherosclerosis, cancer, aging and several other conditions, including inflammatory disease.