Bladder Cancer Screening in Aluminum Smelter Workers

Bladder cancer is the fourth and ninth most common cancer in men and women, respectively, in the United States. An estimated 74,690 people (56,205 men and 18,484 women) will be diagnosed with and 15,210 men and women will die from bladder cancer in 2014.1 Recognized risk factors for bladder cancer include increased age, male sex, white race, smoking, family history, urinary tract infections, drugs, personal history of bladder cancer, and occupational exposures.2 Estimates suggest that between 5% and 25% of bladder cancer incidence is attributable to occupational exposures.3 Consequently, interest has mounted for implementation of bladder cancer screening among high-risk populations including industrial workers exposed to bladder carcinogens in the workplace. Epidemiologic studies of aluminum smelter workers have demonstrated an association between coal tar pitch volatiles (CTPVs) generated during aluminum reduction and bladder cancer.4–8 Coal tar pitch volatiles contain many low molecular weight polycyclic aromatic hydrocarbons (PAHs). Polycyclic aromatic hydrocarbons are lipophilic nonpolar chemicals comprising two or more benzene rings formed as a result of pyrolytic processes, in particular the incomplete combustion of organic materials.6 Some PAHs in CTPV are recognized carcinogens.9 Benzo(a)pyrene (BaP), a specific carcinogenic PAH, and benzene soluble materials (BSM), which include all PAHs present and other benzene soluble compounds, have consistently been found in CTPV10,11; therefore, BaP and BSM are often used as surrogates or indicator compounds for the presence of PAHs in the work environment. Theriault reported on a bladder cancer screening program consisting of annual urine cytology initiated in a cohort of current aluminum smelter workers with at least a 10-year history of CTPV exposure associated with aluminum smelting and later expanded to include workers with at least 5 years of exposure.12 Results of this screening program showed trends toward a higher proportion of early-stage bladder cancer at diagnosis (77% vs 67%) and an increased 5-year survival (rate ratio, 0.54; confidence interval [CI], 0.20 to 1.48) after the screening program was instituted; however, these differences were not statistically significant, and the authors concluded that these results did not encourage an optimistic view of screening effectiveness in the population. Similar to the aforementioned study, most earlier screening protocols for bladder cancer primarily included testing for blood in the urine (hematuria) and/or urine cytology. Unfortunately, hematuria has a relatively low sensitivity and specificity, whereas urinary cytology, although highly specific, has poor sensitivity.13,14 Cystoscopy, although very accurate and considered the criterion standard for the detection of bladder tumors, is an invasive and expensive procedure with complications including intense discomfort as well as bleeding, infections, and mechanical lesions.15 Given these limitations, the focus has turned to identification of more sensitive and specific molecular markers for detection and surveillance of bladder cancer.16–19 One of the earlier tumor markers commercially developed and approved by the United States Food and Drug Administration for bladder cancer surveillance was the ImmunoCyt test (subsequently commercialized under two names: ImmunoCyt/uCyt+). This immunofluorescence assay uses three monoclonal antibodies directed against transitional cell carcinoma antigens in exfoliated cells for the detection of cellular markers that are relatively specific for bladder cancer.20 In a study assessing the sensitivity and specificity of 18 bladder tumor markers including ImmunoCyt/uCyt+, the authors concluded that ImmunoCyt/uCyt+ was one of the six promising markers for surveillance of patients for recurrent bladder cancer.21 Another report comparing ImmunoCyt/uCyt+ alone and in combination with urine cytology to five other commercially available urine tumor markers concluded that the combination of ImmunoCyt/uCyt+ with urine cytology offered a superior sensitivity to the other tests.22 Although the primary focus of many reports assessing various biomarkers to screen for bladder cancer has been on surveillance of bladder cancer recurrence in patients, a few studies have used different combinations of biomarkers for surveillance of high-risk occupational cohorts. In one recent study, bladder cancer screening was instituted in 76 workers exposed to 4, 4-methylenebis (2-chloroaniline) (MBOCA), a synthetic chemical used in the production of castable polyurethane parts. Ninety-two other workers who were not involved in the MBOCA manufacturing process served as controls. Urine occult blood tests, urine cytology, tests for tumor marker nuclear matrix protein 22 (NMP22), which uses two mononuclear antibodies, and abdominal ultrasonography were performed in all participants. This study identified one worker with confirmed bladder cancer; however, the prevalence of atypical urine cells, the NMP22 tumor marker, and positive occult blood were not significantly different between the MBOCA-exposed workers and nonexposed workers.23 In another study, a prospective cohort of 1323 male workers with former exposure to aromatic amines was screened for bladder cancer between 2003 and 2010. Using a combination of annual tests for hematuria, quantitative determination of NMP22, UroVysion test (a fluorescence in situ hybridization assay that assesses chromosomal instability in urothelial cells), and urine cytology, 15 bladder tumors were detected in 14 participants.24 Between 2006 and 2008, 171 male workers from an Italian coke plant with a median exposure duration to PAHs of 16 years were screened for bladder cancer using a medical protocol that included urine analysis, urine cytology, and urine ImmunoCyt/uCyt+. Workers with positive results on at least one of the urinary markers underwent urinary ultrasonography and cystoscopy. Overall, 12% of the workers tested positive on at least one urinary marker. Nevertheless, evidence of bladder cancer was not confirmed by cystoscopy and ultrasonography. The authors reported a specificity of urine analysis, cytology, and ImmunoCyt/uCyt+ of 98%, 96%, and 92%, respectively. Although no increased risk for bladder cancer was seen among the coke workers evaluated, the result was considered preliminary because of reported study limitations, including the small number of workers enrolled in the surveillance program, the analysis based on only one assessment with no follow-up available, and the relatively short duration of PAH exposure in these workers.25 We present the results of a bladder cancer surveillance program conducted between January 2000 and December 2010 in a cohort of aluminum smelter workers in the United States who were employed by a single company. Our objective in this report was to establish the sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of the bladder cancer screening protocol in the context of the observed risk of bladder cancer in the cohort under surveillance.