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Carbonic Anhydrase IX Expression, a Novel Surrogate Marker of Tumor Hypoxia, Is Associated With a Poor Prognosis in Non–Small-Cell Lung Cancer

From the Departments of Oncology, Pathology, and Epidemiology, University Hospitals of Leicester NHS Trust; Imperial Cancer Research Fund, Molecular Oncology Unit, Institute of Medicine, John Ratcliffe Hospital, Oxford, United Kingdom; and Institute of Virology, Slovak Academy of Sciences, Slovak Republic.

Address reprint requests to Kenneth J. O’Byrne, MD, University Hospitals of Leicester NHS Trust, Leicester LE1 5WW, United Kingdom; email: ken.obyrne{at}uhl-tr.nhs.uk.

Purpose: To evaluate carbonic anhydrase (CA) IX as a surrogate marker of hypoxia and investigate the prognostic significance of different patterns of expression in non–small-cell lung cancer (NSCLC).

Methods: Standard immunohistochemical techniques were used to study CA IX expression in 175 resected NSCLC tumors. CA IX expression was determined by Western blotting in A549 cell lines grown under normoxic and hypoxic conditions. Measurements from microvessels to CA IX positivity were obtained.

Results: CA IX immunostaining was detected in 81.8% of patients. Membranous (m) (P = .005), cytoplasmic (c) (P = .018), and stromal (P < .001) CA IX expression correlated with the extent of tumor necrosis (TN). The mean distance from vascular endothelium to the start of tumor cell positivity was 90 µm, which equates to an oxygen pressure of 5.77 mmHg. The distance to blood vessels from individual tumor cells or tumor cell clusters was greater if they expressed mCA IX than if they did not (P < .001). Hypoxic exposure of A549 cells for 16 hours enhanced CA IX expression in the nuclear and cytosolic extracts. Perinuclear (p) CA IX (P = .035) was associated with a poor prognosis. In multivariate analysis, pCA IX (P = .004), stage (P = .001), platelet count (P = .011), sex (P = .027), and TN (P = .035) were independent poor prognostic factors.

Conclusion: These results add weight to the contention that mCA IX is a marker of tumor cell hypoxia. The absence of CA IX staining close to microvessels suggests that these vessels are functionally active. pCA IX expression is representative of an aggressive phenotype.

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