Sibtain, A; (2006) The evaluation of hypoxia in human bladder cancer using intrinsic and extrinsic markers. Doctoral thesis , UCL (University College London).

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Abstract

Hypoxia has been evaluated in a series of human bladder carcinomas using pimonidazole. The relationships of hypoxia with vascularity and with proliferation have been explored. Two intrinsic markers of hypoxia have been validated against pimonidazole and then used to assess the impact of hypoxia on a cohort of bladder tumours treated with a hypoxia modifying treatment stratagem. Thirty-one patients with confirmed transitional cell carcinoma of the bladder received pimonidazole before transurethral resection of the tumour. Sections from 26 tumours were stained for pimonidazole. The median hypoxic fraction was 9% (range 0 to 38%). Twenty-one tumours were double stained for pimonidazole with Ki67 (proliferation), and pimonidazole with CD31/34 (vascularity). Most staining was distant from vessels (median 100um). Some hypoxia was close to vessels (<40um), suggesting a perfusion limiting mechanism in these areas. Dual staining for pimonidazole and proliferation showed a predominantly inverse relationship between these factors. However, some hypoxic regions of less than 40um from a vessel had a higher proliferative index than those further away from vessels Having confirmed GLUT1 and CA9 as appropriate intrinsic markers for hypoxia, archived samples of bladder carcinoma from 64 patients treated with ARCON were obtained. Sections were stained for GLUT1, CA9, Ki67 and CD31/34 and analysed as above. The median follow up time was 24 months The median stained fraction for GLUT1 was 6.5% (range 0 to 62%) and for CA9 was 3.5% (range 0 to 67%). Those patients above the median (more hypoxic tumours) for each marker had a statistically significantly poorer cause specific survival (GLUT1 p<0.005, CA9 p<0.003) but not local recurrence or metastasis free survival, analysed with a log rank test. A multivariate analysis, accounting for stage, age, grade, Ki67 index and vascularity confirmed hypoxic fraction as an independent factor in cause specific survival (GLUT1 p<0.02, CA9 p<0.03). In conclusion, hypoxia is a significant factor in bladder cancer, and is quantifiable with both extrinsic and intrinsic markers. Staining patterns are consistent with diffusion limited and perfusion limited mechanisms of hypoxia. Proliferation is reduced in hypoxic areas but less so in those that are acutely hypoxic. In a cohort of patients with bladder cancer treated with ARCON, patients with more hypoxic tumours, assessed with intrinsic markers, tend to a poorer cause specific survival.

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