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Journal of Clinical Oncology, Vol 26, No 22 (August 1), 2008: pp. 3809-3811 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.17.6511
Carbonic Anhydrase IX Expression in Clear Cell Renal Cell Carcinomas Negatively Correlates With the Proportion of the Granular Cell ComponentDepartment of Pathology and Molecular Medicine, Charles University, Second Medical School, University Hospital Motol, Prague, Czech Republic
Department of Urology, Charles University, Second Medical School, University Hospital Motol, Prague, Czech Republic
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic
Department of Pathology and Molecular Medicine, Charles University, Second Medical School, University Hospital Motol, Prague, Czech Republic To the Editor: We read with great interest an article by Leibovich et al1 addressing the expression of carbonic anhydrase IX (CAIX) in clear cell renal cell carcinomas (ccRCC). CAIX is a catalytically active cell membrane isoform of carbonic anhydrase, which was unexpectedly discovered during the virologic research2 and may be ectopically expressed by various tumor cells. The authors evaluated its use as a prognostic marker in ccRCC and presented crucial facts for the interpretation of CAIX immunohistochemistry with the mouse monoclonal antibody M75. Importantly, they identified the correlation among the low level of CAIX expression and several histopathologic indicators of poor prognosis, including advanced nuclear grade, as was confirmed recently using a polyclonal rabbit anti-CAIX antibody NB100-417.3 Although Leibovich et al observed heterogeneity of the immunostaining for CAIX in the majority of ccRCC, the detailed histologic features of neoplastic cells with variable or absent expression of CAIX were not reported in their article. In our opinion, some cases of heterogeneous expression of CAIX could be explained by an admixture of tumor cells with finely granular eosinophilic cytoplasm, which harbor high numbers of mitochondria.4 The variable immunoreactivity for CAIX in this variant of ccRCC was observed previously,5 it was confirmed by reverse transcription polymerase chain reaction assays,6,7 but it has not been systematically analyzed to date. The granular cell component occurs commonly in ccRCC,8 usually manifesting a higher nuclear grade than the clear-cell part of the tumor,8,9 and therefore it could be interpreted as a sign of tumor dedifferentiation,9 with a possible impact on the patient's prognosis. This could be the reason why, in the study by Leibovich et al, the low immunoreactivity for CAIX failed to independently predict an increased risk of a patient's death after adjusting for prognostically relevant histopathologic features including the nuclear grade, although it correlated univariately with a shorter survival time. Similar neoplastic cells with eosinophilic cytoplasm occur frequently in papillary8 and chromophobe4,8 RCCs and their presence is a basic sign for the diagnosis of renal oncocytoma.8 All of these tumors are known to be negative or inconsistently positive for CAIX.1,5,6,10 In our pilot study of CAIX expression in a spectrum of renal tumors (Table 1), we detected CAIX by means of immunohistochemistry in formalin-fixed, paraffin-embedded tissue sections using the mouse monoclonal antibody clone M75 diluted 1:100. Only membranous staining of tumor cells was considered positive for the evaluation of CAIX expression. The proportion of CAIX-positive neoplastic cells was estimated and the intensity of reaction was semiquantitatively scaled from absent to weak to strong. The typical staining patterns for CAIX in particular renal tumors were subsequently identified (Table 1). The granular cells in ccRCC characteristically showed negativity or only a weak expression of CAIX (Fig 1). Based on these data, the variable extent and intensity of immunostaining for CAIX in ccRCC seems to be associated with the proportion of the granular cell component, and it may be dependent on the numbers of mitochondria in the cytoplasm of neoplastic cells.
Leibovich et al pointed out the influence of the heterogeneous CAIX staining on the interpretation of results of prior studies, in which tissue microarray (TMA) technologies were employed.10-12 An important observation was recently made in this respect. CAIX was used as a prototypic marker of tumor hypoxia in cervical carcinoma,13 but after the correlation with the direct partial pressure of oxygen measurement in tissue sections and simulation of TMA technique, the distributional heterogeneity of CAIX produced a high sampling error. The size of the tissue sample was therefore recognized to be the major factor affecting accuracy of the observation. In the case of ccRCC, the presence of tumor cells with granular cytoplasm in the tissue sample obtained by TMA technique could probably affect results of the study significantly. Therefore, we cannot fully agree with Leibovich et al that CAIX could be used as a complementary marker for the histopathologic evaluation of small renal mass biopsies. The authors propose that patients with more than 30% CAIX expression in their renal tumors harbor ccRCC rather than papillary RCC or chromophobe RCC. By analogy with the TMA technique, this could be misleading in small, poorly representative tissue specimens taken from ccRCC with an increased number of granular neoplastic cells. Because of a high risk of sampling error, the inclusion of CAIX immunohistochemistry in the diagnostic algorithm of renal tumors composed of cells with granular eosinophilic cytoplasm should be avoided. Given that these cells may be present in all common types of RCC (clear cell, papillary, and chromophobe) as well as in renal oncocytomas, the significance of CAIX immunohistochemistry for the differential diagnosis of renal tumors remains limited. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
ACKNOWLEDGMENTS Supported by the research project of the Ministry of Health of the Czech Republic VZ FNM 00000064203. REFERENCES
1. Leibovich BC, Sheinin Y, Lohse CM, et al: Carbonic anhydrase IX is not an independent predictor of outcome for patients with clear cell renal cell carcinoma. J Clin Oncol 25:4757-4764, 2007 2. Závada J, Zavadova Z, Pastorekova S, et al: Expression of MaTu-MN protein in human tumor cultures and in clinical specimens. Int J Cancer 54:268-274, 1993[Medline] 3. 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 32:377-382, 2008[Medline] 4. Tickoo SK, Lee MW, Eble JN, et al: Ultrastructural observations on mitochondria and microvesicles in renal oncocytoma, chromophobe renal cell carcinoma, and eosinophilic variant of conventional (clear cell) renal cell carcinoma. Am J Surg Pathol 24:1247-1256, 2000[Medline] 5. Liao SY, Aurelio ON, Jan K, et al: Identification of the MN/CA9 protein as a reliable diagnostic biomarker of clear cell carcinoma of the kidney. Cancer Res 57:2827-2831, 1997 6. Murakami Y, Kanda K, Tsuji M, et al: MN/CA9 gene expression as a potential biomarker in renal cell carcinoma. BJU Int 83:743-747, 1999[CrossRef][Medline] 7. McKiernan JM, Buttyan R, Bander NH, et al: Expression of the tumor-associated gene MN: A potential biomarker for human renal cell carcinoma. Cancer Res 57:2362-2365, 1997 8. Murphy WM, Grignon DJ, Perlman EJ: Tumors of the kidney, bladder, and related urinary structures (AFIP Atlas of Tumor Pathology, 4th Series). Washington, DC, American Registry of Pathology 2004, pp 109-136 9. Hes O, Michal M, Sulc M, et al: Glassy hyaline globules in granular cell carcinoma, chromophobe cell carcinoma, and oncocytoma of the kidney. Ann Diagn Pathol 2:12-18, 1998[Medline] 10. Sandlund J, Oosterwijk E, Grankvist K, et al: Prognostic impact of carbonic anhydrase IX expression in human renal cell carcinoma. BJU Int 100:556-560, 2007[CrossRef][Medline] 11. 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 9:802-811, 2003 12. Bui MH, Visapaa H, Seligson D, et al: Prognostic value of carbonic anhydrase IX and KI67 as predictors of survival for renal clear cell carcinoma. J Urol 171:2461-2466, 2004[CrossRef][Medline] 13. Iakovlev VV, Pintilie M, Morrison A, et al: Effect of distributional heterogeneity on the analysis of tumor hypoxia based on carbonic anhydrase IX. Lab Invest 87:1206-1217, 2007[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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