Carbonic anhydrase IX, CAIX

Carbonic anhydrase IX is one of four members of the transmembrane carbonic anhydrase family, catalyzing the reversible hydration and transmembrane transportation of carbon dioxide and the regulation of pH15. It is a downstream molecules in the Hippel-Lindau hypoxia inducible factor pathway, implicated in the pathogenesis of clear cell renal cell carcinoma. In tumours, the role in modulating pH is important under conditions of tissue hypoxia9,11.

Immunohistochemical expression

• Normal tissues: gastric mucosa11, biliary tract, small intestine

• Many carcinomas9,15,16 including breast4,5,20, nasopharynx6, oesophagus19, lung10,18, colorectum17, uterine cervix12,13, bladder7 and ovary8. In the uterine cervix, staining is seen in CIN, CGIN and carcinoma, and also in adjacent apparently normal epithelium12.

• Soft tissue sarcomas14.

• Clear cell carcinoma of the kidney but not other renal carcinomas. Two antibodies have been compared and show to give similar levels of staining:

Diagnostic utility

• In breast carcinoma, CAIX expression is associated with oestrogen-receptor negativity, high grade and worse prognosis4,5.

• In renal cell carcinoma, expression of high CAIX expression predicts a good prognosis3. It also predicts the outcome of Interleukin 2 therapy and subsequent survival2.

• Over-expression in nasopharyngeal carcinoma is associated with a worse prognosis6.

• In bladder cancer, CAIX expression is associated with a worse prognosis7.

• In uterine cervical squamous cell cancer, CAIX expression is associated with a worse prognosis13.

• In non-small cell carcinoma of the lung, CAIX expression is associated with a high proliferation index and worse prognosis10,18.

• In deep, large, high-grade soft tissue sarcoma, CAIX expression predicts for poor prognosis14.

References

1 Al-Ahmadie HA, Alden D, Qin LX, et al. Carbonic anhydrase IX expression in clear cell renal cell carcinoma: an immunohistochemical study comparing 2 antibodies. Am J Surg Pathol 2008; 32:377-82

2 Atkins M, Regan M, McDermott D, et al. Carbonic anhydrase IX expression predicts outcome of interleukin 2 therapy for renal cancer. Clin Cancer Res 2005; 11:3714-21 FULL TEXT

3 Bui MH, Seligson D, Han KR, et al. Carbonic anhydrase IX is an independent predictor of survival in advanced renal clear cell carcinoma: implications for prognosis and therapy. Clin Cancer Res 2003; 9:802-11 FULL TEXT

4 Chia SK, Wykoff CC, Watson PH, et al. Prognostic significance of a novel hypoxia-regulated marker, carbonic anhydrase IX, in invasive breast carcinoma. J Clin Oncol 2001; 19:3660-8 FULL TEXT

5 Generali D, Fox SB, Berruti A, et al. Role of carbonic anhydrase IX expression in prediction of the efficacy and outcome of primary epirubicin/tamoxifen therapy for breast cancer. Endocr Relat Cancer 2006; 13:921-30 FULL TEXT

6 Hui EP, Chan AT, Pezzella F, et al. Coexpression of hypoxia-inducible factors 1alpha and 2alpha, carbonic anhydrase IX, and vascular endothelial growth factor in nasopharyngeal carcinoma and relationship to survival. Clin Cancer Res 2002; 8:2595-604 FULL TEXT

7 Hussain SA, Palmer DH, Ganesan R, et al. Carbonic anhydrase IX, a marker of hypoxia: correlation with clinical outcome in transitional cell carcinoma of the bladder. Oncol Rep 2004; 11:1005-10

8 Hynninen P, Vaskivuo L, Saarnio J, et al. Expression of transmembrane carbonic anhydrases IX and XII in ovarian tumours. Histopathology 2006; 49:594-602

9 Ivanov S, Liao SY, Ivanova A, et al. Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. Am J Pathol 2001; 158:905-19 FULL TEXT

10 Kim SJ, Rabbani ZN, Vollmer RT, et al. Carbonic anhydrase IX in early-stage non-small cell lung cancer. Clin Cancer Res 2004; 10:7925-33 FULL TEXT

11 Lam JS, Pantuck AJ, Belldegrun AS, et al. G250: a carbonic anhydrase IX monoclonal antibody. Curr Oncol Rep 2005; 7:109-15

12 Liao SY, Brewer C, Zavada J, et al. Identification of the MN antigen as a diagnostic biomarker of cervical intraepithelial squamous and glandular neoplasia and cervical carcinomas. Am J Pathol 1994; 145:598-609 FULL TEXT

13 Loncaster JA, Harris AL, Davidson SE, et al. Carbonic anhydrase (CA IX) expression, a potential new intrinsic marker of hypoxia: correlations with tumor oxygen measurements and prognosis in locally advanced carcinoma of the cervix. Cancer Res 2001; 61:6394-9 FULL TEXT

14 Maseide K, Kandel RA, Bell RS, et al. Carbonic anhydrase IX as a marker for poor prognosis in soft tissue sarcoma. Clin Cancer Res 2004; 10:4464-71 FULL TEXT

15 Potter CP,Harris AL. Diagnostic, prognostic and therapeutic implications of carbonic anhydrases in cancer. Br J Cancer 2003; 89:2-7

16 Robertson N, Potter C,Harris AL Role of carbonic anhydrase IX in human tumor cell growth, survival, and invasion. Cancer Res 2004; 64:6160-5 FULL TEXT

17 Saarnio J, Parkkila S, Parkkila AK, et al. Immunohistochemical study of colorectal tumors for expression of a novel transmembrane carbonic anhydrase, MN/CA IX, with potential value as a marker of cell proliferation. Am J Pathol 1998; 153:279-85 FULL TEXT

18 Swinson DE, Jones JL, Richardson D, et al. Carbonic anhydrase IX expression, a novel surrogate marker of tumor hypoxia, is associated with a poor prognosis in non-small-cell lung cancer. J Clin Oncol 2003; 21:473-82 FULL TEXT

19 Turner JR, Odze RD, Crum CP, et al. MN antigen expression in normal, preneoplastic, and neoplastic esophagus: a clinicopathological study of a new cancer-associated biomarker. Hum Pathol 1997; 28:740-4

20 Wykoff CC, Beasley N, Watson PH, et al. Expression of the hypoxia-inducible and tumor-associated carbonic anhydrases in ductal carcinoma in situ of the breast. Am J Pathol 2001; 158:1011-9 FULL TEXT

This page last revised 10.5.2008.

5SMUHT/PW Bishop