Epidemiology of urothelial carcinoma

Transcription

1 International Journal of Urology (2017) 24, doi: /iju Review Article Epidemiology of urothelial carcinoma Jun Miyazaki and Hiroyuki Nishiyama Department of Urology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan Abbreviations & Acronyms BEN = Balkan endemic nephropathy CI = confidence interval HNPCC = hereditary nonpolyposis colorectal carcinoma HR = hazard ratio OR = odds ratio SMR = standardized mortality ratio UBC = urinary bladder cancer UTUC = upper tract urothelial carcinoma Correspondence: Jun Miyazaki M.D., Ph.D., Department of Urology, Faculty of Medicine, University of Tsukuba, Tennodai, Tsukuba, Ibaraki , Japan. jmiyazaki@md.tsuk uba.ac.jp Received 27 February 2017; accepted 9 April Online publication 21 May 2017 Abstract: The epithelium lining is defined as the mucosal surfaces of the renal collecting tubules, calyces and pelvis, as well as the ureter, bladder and urethra. The term urothelium is used to refer to these surfaces. Upper tract urothelial carcinoma is a rare subset of urothelial cancers with a poor prognosis. Urinary bladder cancer is the most common malignancy involving the urinary system. Upper tract urothelial carcinoma is more common in men than in women, with a male-to-female ratio of 2:1. The incidence of urinary bladder cancer is also higher in men. Cigarette smoking and occupational exposure are the main upper tract urothelial carcinoma and urinary bladder cancer risk factors, while other factors are more specific to the carcinogenesis of upper tract urothelial carcinoma (i.e. Balkan endemic nephropathy, Chinese herb nephropathy). In Egypt until recent years, urinary bladder cancer was the most frequently diagnosed cancer due to Schistosoma haematobium. Substantial knowledge exists regarding the causes of upper tract urothelial carcinoma and urinary bladder cancer, and epidemiological studies have identified various chemical carcinogens that are believed to be responsible for most cases of urothelial carcinoma. In the era of precision medicine, genetic effects might play a direct role in the initiation and progression of urothelial carcinoma. Key words: epidemiology, upper tract urothelial carcinoma, urinary bladder cancer, urothelial carcinoma. Introduction The mucosal surfaces of the renal collecting tubules, calyces and pelvis, as well as the ureter, bladder and urethra all have the same embryologic origin, and the term urothelium is used to delineate this lining surface epithelium. Nearly all cases of urothelial carcinoma are UBCs, whereas UTUC accounts for just 5 10% of all urothelial malignancies. 1 Studies of UTUC and UBC have identified multiple risk factors, the most important of which are cigarette smoking and various occupational exposures. Numerous other factors have also been identified in cases of UTUC and UBC, although the interpretation of the evidence is frequently confounded. In the present non-systematic review, we comprehensively summarize the epidemiological features of UTUC and UBC. Upper tract urothelial carcinoma Incidence and prevalence (Table 1) A UTUC can be defined as any neoplastic growth that affects the lining of the urinary tract from the calyces to the distal ureter. Tumors of the upper urinary tract are nearly twice as common in men compared with women, with a mean age at diagnosis of 73 years. 2 In a Swedish patient series, the percentage of UTUCs that were bilateral was 1.6%, preceded in 80% of the cases by a bladder cancer diagnosis. Fortunately, synchronous bilateral urothelial upper urinary tract tumors are very rare. 3 Primary tumors arising in the renal pelvis include urothelial carcinomas, squamous cell carcinomas and adenocarcinomas. Squamous cell carcinomas account for approximately 8% of tumors of the renal pelvis. 4 These tumors are associated with a poorer prognosis than urothelial carcinomas, because they tend to be sessile and deeply invasive at presentation. Squamous cell carcinomas have been associated with antecedent calculi or chronic infection The Japanese Urological Association

2 Epidemiology of urothelial carcinoma Table 1 Risk factors for developing UTUC and UBC Exposure type RR ORs HRs Incidence Reference(s) UTUC Cigarettes , Aromatic amines Phenacetine BEN UTUC had an 11.2-fold increased incidence in endemic than in non-endemic areas 11,54 Chinese herbs nephropathy 40 45% of Chinese herb nephropathy patients displayed UTUC 55 UBC Cigarettes Occupation Thiazolidinediones In Japan, the number of deaths as a result of renal pelvic tumors went from 1281 in 2002 to 1200 in 2006 and 1558 in Similarly, the number of deaths as a result of a ureteral tumor also showed an increasing trend with 1055 in 2006 and 1593 in 2010, compared with 852 in UTUCs show behaviors that are similar to those of tumors arising in the bladder. To date, much of the decision-making in UTUC cases comes from knowledge acquired in UBC cases, because of the relative rarity of UTUCs. A large amount of evidence has proven that UTUCs and UBCs have common features, but differ as well to a significant degree. 7 For example, UTUCs are common in specific disorders, including Balkan endemic nephropathy. 8 Chinese herb nephropathy is also a risk factor for UTUC, but not for UBC. 9 Environmental factors Balkan endemic nephropathy is characterized by a degenerative interstitial nephropathy. It has been observed in individuals living in Balkan countries (i.e. Bulgaria, Greece, Romania, the former Yugoslavia), and it is associated with the development of urothelial tumors of the renal pelvis and ureter. In that geographic region, these urothelial tumors account for almost 50% of all renal cancers. Curiously, the bladder cancer incidence is not affected. Balkan endemic nephropathy is familial, but not obviously inherited, suggesting an environmental etiology. Grollman et al. reported that dietary exposure to aristolochic acid (a potent carcinogen derived from Aristolochia plants) might be responsible. 10 Poor outcomes are seen in women (HR 2.2), in individuals with a tumor >3 cm (HR 2.8) and in those with stage T3 or T4 disease (HR 3.1). 11 Chinese herb nephropathy can cause a progressive renal fibrosis that is frequently associated with urothelial malignancy of the renal pelvis. 12 Balkan endemic nephropathy and Chinese herb nephropathy are the same disease, and they are specifically related to UTUC. 13 They are characterized by a mutation of the p53 gene as a consequence of exposure to aristolochic acid. A significant use of aristolochic acid from Aristolochia plants has been documented in Taiwan, where the incidence of UTUC is estimated to be approximately 20 25% of all urothelial cancers, the highest worldwide. 14 In contrast, unusually high incidences of UTUC have been reported from the endemic area for blackfoot disease of southern Taiwan, and the arsenic-contaminated water was considered to be the reason for this prevalence. This geographical area corresponds to the endemic location of blackfoot disease, which is known to be a type of vasculitis. This vasculitis is caused by chronic exposure to arsenic pollution of water in artesian wells. 15,16 However, the relationship between blackfoot disease and UTUC remains unclear. 17 Another report suggested that exposure to arsenic is associated with the development of upper urinary tract cancer in Taiwan. 18 Cigarette smoke Current tobacco smoking is a significant risk factor for an earlier diagnosis of UTUC. Smoking exposure is complex and linked to multiple inhaled toxic substances (e.g. aromatic amine). As for the effects of smoking on UTUC, the relative risk for developing UTUC among smokers was reported to be 2.5- to 7-fold higher than that for nonsmokers, 18,19 and the risk of developing UTUC appears to be twice as common for individuals who smoke >40 cigarettes per day compared with those who smoke <20 cigarettes per day. 20 The effects of smoking on the age at the diagnosis of UTUC remain controversial In Japan, the mean age at the diagnosis of UTUC is approximately 5 years earlier for current smokers compared with current non-smokers (P < ). 24 It should also be noted that the impact of smoking on UTUC outcomes seems to be gender-specific. Women who are current and heavy long-term smokers were reported to have worse survival outcomes than their male counterparts. 23 Analgesics Phenacetin, an analgesic that was widely used for 40 years, has been recognized as a risk factor for UTUC. 3 Phenacetin indirectly causes carcinogenesis by inducing nephrotoxicity through papillary necrosis. This could promote carcinogenesis or act as a cofactor in the presence of chronic irritation, infection or smoking. 25 The use of phenacetin was progressively abandoned in the 1980s and replaced by acetaminophen, which does not increase the cancer risk The Japanese Urological Association 731

3 J MIYAZAKI AND H NISHIYAMA Genetic effects Rare cases of UTUC linked to HNPCC (also known as Lynch syndrome) have also been reported. Patients with Lynch syndrome have abnormalities in DNA mismatch repair. These abnormalities are classically associated with colorectal and endometrial tumors. These abnormalities were also associated with urothelial neoplasms, particularly of the ureter and renal pelvis. 26 Patients at risk have an approximately 22-fold increased relative risk of developing UTUC. 27 The lifetime risk for urological cancer has been estimated to be approximately 8% by age 70 years, 26 and that is why some guidelines and experts recommend that all UTUC patients should be screened for HNPCC spectrum disease though a short interview, and should undergo DNA sequencing if they fulfill all criteria for HNPCC. 28 If DNA sequencing confirms the diagnosis of HNPCC syndrome, patients should undergo a clinical evaluation for other HNPCC-related cancers, a close follow up and familial genetic counseling. 27 Urinary bladder cancer Incidence and prevalence (Table 1) UBC is the most common malignancy involving the urinary system. Urothelial carcinoma is the predominant histological type, accounting for approximately 90% of bladder cancers. In areas of the world other than Western Europe (such as the Middle East), non-urothelial histologies are more frequent as a result of the prevalence of schistosomiasis. From a clinical standpoint, UBCs are classified as nonmuscle-invasive bladder cancer or muscle-invasive bladder cancer, because invasion of the muscle layer is the major determinant of carrying out a cystectomy. The 5-year relative survival rate for patients with UBC rages from 97% (stage I) to 22% (stage IV). UBCs are typically diagnosed in older individuals, with a median age at diagnosis of 69 years in men and 73 in women. 29 In Japan in 2009, bladder cancer was the eighth most common cancer in men and the seventeenth most common cancer in women. The age-standardized bladder cancer incidence rates (standard population: world population) for men and women were 8.6 and 1.8, respectively (standard population: in the Japanese 1985 model population, the incidence rate for men was 12.7, and that for women was 2.7). 30 Bladder cancer occurred 4.7-fold more frequently in men. Environmental factors Infection with Schistosoma haematobium is most prevalent in East Africa and the Middle East, where it is responsible for the high incidence of bladder cancer. 31,32 In Egypt, where public health measures have led to a dramatic decrease in the prevalence of schistosomiasis, there has been a subsequent decrease in the incidence of schistosomal bladder cancer. 33 Thus, the epidemiology of bladder cancer in Egypt has become more similar to that of bladder cancer in Western Europe and the USA, with an older age of onset and a predominance of urothelial carcinoma. The median age at the diagnosis of schistosomal bladder cancer is in the 40s. 34 Cigarette smoking Studies of urothelial bladder cancer have identified multiple risk factors, the most important of which are cigarette smoking and various occupational exposures. 35,36 The carcinogenic compounds present in cigarettes that are responsible for bladder cancer have not been definitively identified. There are over 60 known carcinogens and reactive oxygen species in cigarettes, and it is also evident that cigarette smoke can induce changes in the DNA damage response machinery, which can additively or synergistically impair the host response to carcinogens. 37,38 The relationship between smoking and the risk of bladder cancer is illustrated by a prospective analysis in the National Institutes of Health ARP Diet and Health Study Cohort. 35 This database included over individuals followed from 1995 to 2006 in the USA. For current smokers, there was a significant increase in the risk of bladder cancer for both men and women (multivariate adjusted HRs 3.89 and 4.65, respectively). Although there was an attenuation risk in the former smokers, the risk remained significantly elevated (HR 2.14 and 2.52 for men and women, respectively). A meta-analysis that included data from 88 studies found that the relative risk values of bladder cancer for all smokers, current smokers, and former smokers compared with nonsmokers were 2.62 (95% CI ), 3.49 (95% CI ) and 2.07 (95% CI ), respectively. 36 The extent of smoking appears to be related to the aggressiveness of bladder cancer. In a study of 740 patients diagnosed over a 22-year period, heavy smokers ( 30 pack years) were more likely to have a high-grade tumor and to have muscle-invasive disease at their original presentation compared with non-smokers. 39 Smoking cessation also appears to decrease the recurrence rate for patients with non-muscle-invasive bladder cancer even after the diagnosis. 40 In both men and women, the onset of bladder cancer is approximately 6 years earlier (6.1 years in men and 5.9 years in women) for current smokers than for current non-smokers. 41 At the time of diagnosis, the tumor stage was significantly higher in the current smokers group. Wilcox et al. evaluated whether smoking status and common adult occupations are associated with time to UBC recurrence for 406 patients with muscle-invasive bladder cancer as part of The Cancer Genome Atlas project, and they found that smoking status impacts the risk of UBC recurrence and that occupation might be related to an increased risk of recurrence. 42 Analgesics A number of studies have documented a decrease in the risk of bladder cancer with the regular use of any non-steroidal antiinflammatory drug, 43 suggesting a protective effect by inhibition of the inflammatory and proliferative response, although other research groups have found no such association. 44 Thiazolidinediones Thiazolidinediones are oral hypoglycemic agents used to treat diabetes mellitus. Some early studies reported that the longterm use of these agents is apparently associated with an The Japanese Urological Association

4 Epidemiology of urothelial carcinoma increased risk of bladder cancer. This association is controversial, and different reports have given conflicting results. A meta-analysis of 18 studies (five randomized clinical trials involving almost 7900 participants and 13 observational studies involving more than 2.6 million patients) showed a significantly higher risk of bladder cancer with an OR of 2.51 (95% CI ) for pioglitazone in the randomized clinical trials, and an OR of 1.21 (95% CI ) for ever users versus non-users in observational studies. The risk appeared to be greatest with >28.0 g of pioglitazone (OR 1.64, 95% CI ) and >2 years of exposure (OR 1.51, 95% CI ). This increased risk was not observed with rosiglitazone. 45 In a large international multipopulation pooled cumulative exposure analysis involving more than 1 million patients with type 2 diabetes and >5.9 million person-years, investigators identified 3248 cases of incident bladder cancer of whom 117 cases were exposed to a thiazolidinedione. With a median follow-up period of years, there was no association between cumulative exposure to pioglitazone or rosiglitazone and bladder cancer after adjusting for age, calendar year, duration of diabetes, and smoking history. 46 Occupational carcinogen exposure Occupations have been linked to an increased risk of bladder cancer. The summary relative risk conferred by occupational exposures range from 1.2 to Aromatic amines, to which exposure occurs in the chemical and rubber industries, are major occupational carcinogens. Dyestuff workers exposed to one or more substances including benzidine, beta-naphthylamine, alpha-naphthylamine and dianisidine were followed completely, and the incidence of urothelial carcinoma was determined by periodic urological screenings. 48 Analyses of site-specific cancer mortality showed a markedly increased risk of bladder carcinoma for individuals engaged in benzidine manufacturing (SMR = 63.6), benzidine use (SMR = 27.0) and beta-naphthylamine manufacture (SMR = 48.4), but not for individuals who were exposed to alpha-naphthylamine. Polycyclic aromatic hydrocarbons, used in aluminum production, coal gasification, coal tars, roofing and carbon black manufacturing, are also associated with UBC risk. 49 Although the relative risk of bladder cancer associated with these occupations is small, the public health impact can be significant, considering the substantial number of people who were and are employed in these occupations. 47 Genetic effects Multiple epidemiological studies have examined the role of genetic factors as risk factors for the development of UBC. Most of these studies identified a small increase in the risk among relatives of individuals with bladder cancer, and the risk appears to be greatest in those whose affected relatives were diagnosed before the age of 60 years. In the Swedish Family History Cancer Database from 1958 to 1996, bladder cancer was identified in a parent offspring pair in 65 families. 50 The risk of bladder cancer was elevated in the offspring of parents with bladder cancer (standardized incidence ratios 1.35 and 2.29 in sons and daughters, respectively). The highest risk was observed in brothers of patients diagnosed before the age of 45 years (standardized incidence ratio 7.3), suggesting an X-linked inheritance. A case control study from the MD Anderson Cancer Center analyzed 713 bladder cancer patients and 658 controls. 51 Probands who had smoked and who had a positive family history of bladder cancer had a fivefold increased risk of developing bladder cancer. In an associated analysis of families of this cohort, the risk of bladder cancer was increased nearly sevenfold in relatives of patients who had been diagnosed with bladder cancer between ages 40 and 65 years who had a history of smoking, compared with never-smokers with a negative family history. The Spanish Bladder Cancer Study analyzed 1158 patients with newly diagnosed bladder cancer and 1244 controls; There was a non-significant increase in the risk of bladder cancer in the patients with a positive family history (OR 2.34, 95% CI ). 52 Conclusion Urothelial carcinoma can be divided mainly into UTUC and UBC, but UTUC and UBC have many different points. Epidemiological studies have identified various chemical carcinogens that are believed to be responsible for most cases of urothelial carcinoma. However, particular environmental factors are specifically associated with UTUC (e.g. phenacetin and aristolochic acid nephropathy). Our understanding of the roles of toxic chemicals in UTUC is still limited, but it is increasingly clear that exposure to such environmental factors is responsible for UTUC. UBC is the most frequent urinary tract malignancy, and cigarette smoke is mostly responsible for UBC in both men and women. Occupational exposure to various chemical carcinogens is also thought to contribute to the development of UBC. It is increasingly clear that interactions between genetic susceptibility and exposure to these environmental factors are responsible for urothelial carcinoma. Conflict of interest None declared. References 1 Siegel RL, Miller KD, Jemal A. Cancer statistics, CA Cancer J. Clin. 2016; 66: Raman JD, Messer J, Sielatycki JA, Hollenbeak CS. Incidence and survival of patients with carcinoma of the ureter and renal pelvis in the USA, BJU Int. 2011; 107: Holmang S, Johansson SL. Synchronous bilateral ureteral and renal pelvic carcinomas: incidence, etiology, treatment and outcome. 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