Additional risk factors associated with more aggressive forms of bladder cancer include neuropathic bladder and associated indwelling catheters;[25,26]Schistosoma haematobium bladder infections (Bilharzial bladder cancer); exposure to the cancer chemotherapy agent cyclophosphamide [28,29] and perhaps other alkylating agents, such as ifosfamide (although the use of mesna in conjunction with these agents may reduce the incidence); and pelvic radiation therapy for other malignancies, such as prostate cancer,[30,31] uterine cancer, and cervical cancer.
Specific genetic mutations associated with bladder cancer include the following:[34,35,36]
- HRAS mutation (Costello syndrome or Faciocutaneoskeletal syndrome).
- RB1 mutation.
- PTEN/MMAC1 mutation (Cowden syndrome).
- NAT2 slow acetylator phenotype.
- GSTM1 null phenotype.
Urothelial tumors other than TCC include adenocarcinoma, SCC, and metastatic adenocarcinoma. Risks for squamous cell tumors in the bladder include indwelling catheters [37,38] and S. haematobium cystitis.
Adenocarcinomas account for less than 2% of primary bladder cancers, including metastases from the rectum, stomach, endometrium, breast, prostate, and ovary.
Although occasional familial clusters have been anecdotally reported [39,40,41] and bladder cancer (as well as upper urinary tract TCC) is part of the Lynch family cancer syndrome II, there is no evidence that tendencies towards developing bladder cancer are inherited.
Seventy percent of patients with bladder cancer have superficial disease at presentation. Hematuria is the most common presenting sign, occurring in about 90% of cases. Hematuria may be intermittent, so a urinalysis without red blood cells does not exclude a diagnosis of urothelial cancer. In patients with macroscopic hematuria, the reported rates of bladder cancer range from 13% to 34.5%.[45,46,47] Other presenting symptoms include dysuria, urinary frequency or urgency, and less commonly, flank pain secondary to obstruction, and pain from pelvic invasion or bone metastases. Diagnosis and staging usually begin with cystoscopy. Full evaluation of the upper and lower urinary tract is required.
More than 90% of bladder cancers diagnosed in the United States are pure TCCs or TCCs mixed with other histologies, primarily SCC, adenocarcinoma, or both. An additional 3% to 4% are pure SCCs, which are approximately twice as likely to occur in women as in men. SCCs also represent a greater proportion of bladder cancers occurring in individuals who have S. haematobium infections of the bladder or who have histories of long-term indwelling urinary catheters, bladder stones, or recurrent bladder infections.[29,37,38]