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Journal of Clinical Oncology, Vol 26, No 18 (June 20), 2008: pp. 3107-3109 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.16.2164
In ReplyDepartment of Urology, Mayo Clinic, Rochester, MN
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
Department of Health Sciences Research, Mayo Clinic, Rochester, MN
Department of Urology, Mayo Clinic, Rochester, MN
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
Institute of Organic Chemistry and Biochemistry, Prague, Czech Republic
Departments of Urology and Immunology, Mayo Clinic, Rochester, MN We appreciate the interest from Pantuck et al and believe that some clarification and additional discussion of the data presented in our article may be of interest. The intent of our study was to provide independent validation of prior investigations2,3 that have suggested that carbonic anhydrase IX (CAIX) status provides prognostic information to improve on standard pathologic and clinical parameters. To our knowledge, our article is the largest reported series of patients with clear cell renal cell carcinoma (ccRCC) examined with immunohistologic staining for CAIX. Our univariate results suggest that patients with low CAIX expression were at increased risk of death from RCC relative to patients with high CAIX expression (risk ratio 1.65; P < .001); however, we did not find that CAIX was an independent predictor of outcome after adjusting for either nuclear grade or coagulative tumor necrosis; two commonly used predictors of ccRCC outcome. Pantuck et al stated: "... statistical significance of this association was lost when simultaneous adjustment was made for TNM stage grouping, nuclear grade, and ECOG PS, leading the authors to criticize the use of CAIX as a prognostic marker for RCC." Although we concur that statistical significance was lost after adjusting for multiple features, we reiterate that our results demonstrate that adjustment for only a single feature, namely nuclear grade, negated the effect of CAIX in predicting outcome. In addition, adjustment for coagulative tumor necrosis (a feature Pantuck et al have similarly found to be of prognostic significance) also abrogated the effect of CAIX in predicting death from RCC. Thus, our results support that each of these commonly used histologic findings carries more prognostic information regarding death from RCC than immunohistochemical determination of CAIX status. Pantuck et al refer to our work as an "outlier" with regard to the published literature on CAIX in RCC. We argue that the field of research pertaining to observations of CAIX in RCC is relatively young, which is supported by the fact that five of the references in the letter by Pantuck et al are from meeting abstracts that have yet to be published. However, given that the combined number of patients in the published studies referenced by Pantuck et al4 is fewer than we have reported in our single study, we believe that our study is more appropriately labeled as "the majority" of the published literature as opposed to "the outlier." The comparison does, however, raise several areas of possible discussion regarding the disparate results, including patient populations and the use of tissue microarrays (TMAs) versus whole tumor sections. In our article, we acknowledged that there is a significant difference in patient populations between our series compared and the study cohorts reported by Pantuck et al,4 which are skewed toward advanced RCC patients treated with immunotherapy. In contrast, our patient population is composed of local patients with lower-stage RCC along with a tertiary referral practice with advanced RCC, more accurately reflecting the expected distribution of stage and grade of ccRCC in an unselected population. Furthermore, it represents a consecutive series of patients who have been observed prospectively using rigorous standards and who have undergone uniform pathologic review by a single expert urologic pathologist. The fact that CAIX has been reported to be an independent predictor of outcome in populations of advanced RCC may be secondary to the treatment offered, as suggested by ourselves as well as by Pantuck et al. Consistent with this, Atkins et al5 have reported a pilot study of 66 selected patients indicating that CAIX may serve as a marker for response to high-dose interleukin-2 therapy and survival for patients with metastatic RCC. Considering the number of advanced patients treated with immunotherapy in the University of California, Los Angeles data,2,3 it is possible that the association of CAIX with survival relates to an interaction with immunotherapy. However, we cannot assess whether CAIX may be a marker for prediction of response to therapy as only 6% of our patients were treated with immunotherapy. In addition, given our observation that CAIX is not prognostic after adjustment for nuclear grade or coagulative tumor necrosis, it is difficult to envision how CAIX expression will ultimately prove itself as an independent predictor of systemic treatment responses for advanced RCC patients. Nevertheless, the results in the study by Atkins et al5 and the unpublished data referenced by Pantuck et al in their letter are exciting, and we hope that they will be confirmed by ongoing and future prospective trials. However, these results have little relevance to our finding that CAIX does not add prognostic ability after considering nuclear grade or coagulative tumor necrosis for patients with surgically treated ccRCC.
Pantuck et al raise an important issue of appropriate cut points for the dichotomous reporting of low versus high CAIX staining. We used a cut point of 85% staining as this has been the convention established by Dr Pantuck's group at University of California, Los Angeles.2,3 Sandlund et al6 state that they arbitrarily chose 0% to 10%, 11% to 90%, and 91% to 100% as their cut points for CAIX staining in ccRCC. We agree that an analysis of alternate thresholds as reported by Sandlund et al or examination of CAIX as a continuous variable would be of value, and we appreciate this opportunity to share these additional data with regard to our original series of 730 ccRCC patients. When examined univariately as a continuous variable, each 10% increase in CAIX expression was associated with an 8% decrease in the risk of death from RCC (risk ratio, 0.92; 95% CI, 0.89 to 0.97; P < .001). However, we once again found that after adjusting for either nuclear grade or coagulative tumor necrosis, CAIX expression was no longer significantly associated with death as a result of RCC (P = .145 and P = .339, respectively). When examined univariately utilizing an alternate cut point similar to Sandlund et al, patients in our cohort whose tumors contained low levels of CAIX expression (defined as Another major difference among the studies relates to the use of TMAs versus whole tumor sections. We found heterogeneity of staining in 55.8% of cases when examining whole tumor sections. We are not familiar with the unpublished data referred to by Pantuck et al. However, the finding that the majority of patients had varied intensity of staining across sections of tumor in our series raises the possibility that small cores of tissue utilized in the construction of a TMA may not be an accurate representation of the percentage of cells that stain positive in larger, whole sections. When a TMA composed of multiple cores of tissue is averaged for each specimen, the assignment of low versus high staining is dependent on the degree of heterogeneity and the appropriate selection of cores to represent the tumor. Whereas the latter can be controlled by careful TMA construction, the former cannot be controlled. This concept is illustrated in Figure 1.
In summary, we have found that CAIX status among patients with ccRCC is associated with death from RCC; however, this association is not significant when considering standard pathologic features such as nuclear grade or coagulative tumor necrosis. We have also shown that this remains true if CAIX is assessed with another arbitrarily chosen cut point of 90% or as a continuous variable. Furthermore, we have demonstrated significant heterogeneity in the expression of CAIX that makes TMA assessment potentially inaccurate. We look forward to additional studies that may confirm the utility of CAIX to predict response to systemic therapy. In the interim, it would be inappropriate to draw strong conclusions from our study that CAIX represents a compelling predictor of systemic treatment responses in advanced RCC patients. In short, we demonstrate that CAIX is not an independent predictor of outcome and cannot advocate CAIX as a general prognostic marker for RCC.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. 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. Bui MHT, 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 3. Bui MHT, 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] 4. Lam JS, Shvarts O, Said JW, et al: Clinicopathologic and molecular correlations of necrosis in the primary tumor of patients with renal cell carcinoma. Cancer 103:2517-2525, 2005[CrossRef][Medline] 5. Atkins M, Regan M, McDermott D, et al: Carbonic anhydrase IX expression predicts outcome of interleukin 2 therapy for renal cancer. Clin Cancer Res 11:3714-3721, 2005 6. 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] Related Correspondence
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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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90%) were 34% more likely to die as a result of RCC compared with patients whose tumors contained 100% CAIX expression (risk ratio, 1.34; 95% CI, 1.04 to 1.72; P = .026). Once again, after adjusting for either nuclear grade or coagulative tumor necrosis, low CAIX expression using this alternative definition was no longer significantly associated with death as a result of RCC (P = .755 and P = .580, respectively). 
