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Journal of Clinical Oncology, Vol 25, No 30 (October 20), 2007: pp. 4757-4764 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.1087 Carbonic Anhydrase IX Is Not an Independent Predictor of Outcome for Patients With Clear Cell Renal Cell Carcinoma
From the Departments of Urology, Health Sciences Research, Laboratory Medicine and Pathology, and Immunology, Mayo Medical School and Mayo Clinic, Rochester, MN; and the Institute of Organic Chemistry and Biochemistry, Prague, Czech Republic Address reprint requests to Eugene D. Kwon, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: kwon.eugene{at}mayo.edu
Purpose: Expression of carbonic anhydrase IX (CAIX) has been reported to be an independent predictor of outcome and is being investigated as a therapeutic target for patients with clear cell renal cell carcinoma (ccRCC). We attempted to validate the prognostic utility of CAIX expression using a large cohort of ccRCC patients with long-term follow-up. Patients and Methods: We identified 730 patients with unilateral, sporadic ccRCC treated surgically between 1990 and 1999. Anti-CAIX monoclonal antibody (clone M75) was used, and tumor specimens were blindly scored for expression levels. Associations of CAIX expression with RCC death were evaluated using Cox proportional hazards regression models.
Results: There were 241 RCC deaths and a median of 9.4 years of follow-up for patients still under observation. CAIX was expressed in 708 (97.0%) of the specimens; 163 tumors (22.3%) exhibited low ( Conclusion: CAIX is strongly expressed by ccRCC. Although CAIX is associated with outcome in patients with ccRCC, it is not an independent prognostic marker. Furthermore, CAIX expression is apparent in extrarenal organs. As such, exploitation of CAIX as a prognostic marker and therapeutic target merits additional consideration.
Although the clinical course of clear cell renal cell carcinoma (ccRCC) can be unpredictable, several tumor and patient-specific indices have been shown to aid in prediction of patient outcome.1-7 Tumor-associated proteins may serve a dual purpose as predictive markers as well as potential targets for therapy to improve management of cancer patients. One such marker is carbonic anhydrase IX (CAIX), a cytosolic transmembrane protein implicated in regulating cell proliferation in response to hypoxia. CAIX can be overexpressed by a number of malignancies, including ccRCC. Liao et al8 first described ubiquitous CAIX protein expression in 40 ccRCC tumors, but only focal expression in the three papillary and two collecting duct tumors studied. Subsequently, Bui et al9 examined tissue microarrays (TMAs) of 321 ccRCC patients treated by nephrectomy and concluded that low CAIX expression (defined as  85% tumor cells positive for CAIX by immunohistochemistry) was an independent predictor of poor prognosis. In a smaller study involving 66 patients, TMA CAIX expression in RCC specimens was reported to predict responses to systemic therapy with interleukin-2 (IL-2).10 Partly on the basis of these observations, there has been interest in developing CAIX as a prognostic and imaging marker for RCC, as well as a tumor-associated target for therapy.11-17 However, information pertaining to the differential expression by RCC histologic subtypes and normal human tissues remains limited, especially in the context of anti-CAIX therapy for the treatment of RCC. Moreover, independent validation of CAIX as a prognostic marker for ccRCC patients has not been reported. Hence, we conducted an investigation of CAIX expression in 933 RCC patients with long-term follow-up, 730 of whom had ccRCC. We report that CAIX expression varies significantly by RCC subtype and that CAIX expression in ccRCC fails as an independent predictor of outcome following multivariate adjustment for conventional prognostic features. We also report high levels of CAIX expression in various extrarenal organs. Thus, we raise concerns that CAIX may have limited utility as an independent prognostic marker and therapeutic target for RCC.
Patient Selection On institutional review board approval, we identified 933 patients treated with radical nephrectomy or nephron-sparing surgery for unilateral, sporadic RCC between 1990 and 1999 from the Mayo Clinic Nephrectomy Registry. Of these, 730 (78.2%) had noncystic ccRCC, 155 (16.6%) had papillary RCC, and 48 (5.1%) had chromophobe RCC. Clinical features studied included age, sex, symptoms at presentation, Eastern Cooperative Oncology Group (ECOG) performance status, and tumor thrombus level. Patients with a palpable mass, abdominal discomfort, gross hematuria, acute onset varicocele, or constitutional symptoms including rash, sweats, weight loss, fatigue, early satiety, and anorexia were considered symptomatic at presentation. Pathologic features included histologic subtype, tumor size, 2002 primary tumor classification, regional lymph node involvement, distant metastases, the 2002 TNM stage groupings, nuclear grade, coagulative tumor necrosis, and sarcomatoid differentiation. To obtain these features, one study pathologist (J.C.C.) reviewed the microscopic slides from all specimens without knowledge of patient outcome or CAIX expression. Disease status and vital status for patients in the Nephrectomy Registry are updated yearly. If a patient has not been seen at the institution in the previous year, the patient is sent a questionnaire. If there is evidence of disease progression in this questionnaire, the date, location, and treatment are verified with the patient's local physician. If a patient has died in the previous year, a death certificate is ordered and the medical history is reviewed by a urologic oncologist to determine cause of death.
CAIX Immunohistochemical Staining and Quantitation
Statistical Methods
Analysis of Normal Tissues
Comparison of CAIX Expression by RCC Subtype CAIX expression varied significantly by RCC subtype. Nearly all (708 patients, 97.0%) of the 730 ccRCC tumors were CAIX positive compared with 36 (23.2%) and two (4.2%) papillary and chromophobe tumors, respectively (P < .001). Although 442 ccRCC specimens (60.6%) had 100% tumor CAIX expression, the highest levels of CAIX expression observed in the papillary and chromophobe specimens were 30% and 5%, respectively. Maximal staining intensity varied by RCC subtype as well, with marked CAIX expression observed in 489 (67.0%) ccRCC tumors compared with only eight (5.2%) and one (2.1%) papillary and chromophobe tumors, respectively (P < .001). No specimen showed CAIX expression in normal renal parenchyma. Representative photomicrographs of each subtype stained for CAIX are depicted in Figure 1.
CAIX Expression in 730 Patients With ccRCC ccRCC has been shown to be more aggressive than papillary and chromophobe RCC, and there are differences in features predictive of outcome among these subtypes.1,2,19-21 Therefore, our analysis of the prognostic impact of CAIX expression was limited to the 730 patients with ccRCC. Average age at surgery was 63 years (range, 25 to 89 years); average tumor size was 7.1 cm (range, 0.2 to 24.0 cm). At last follow-up, 399 patients had died, including 241 who died as a result of RCC at a median of 2.1 years after surgery (range, 0.1 to 14.1 years). Among the 331 patients still alive at last follow-up, the median duration of follow-up was 9.4 years (range, 0.1 to 16.7 years); only 14 patients (4.2%) had fewer than 5 years of follow-up. Cancer-specific survival rates at 5 and 10 years following surgery were 73.6% (SE, 1.7%; No. still at risk, 461) and 65.1% (SE, 2.0%; No. still at risk, 185), respectively. Among the 708 (97.0%) ccRCC tumors with CAIX tumor expression, median level of expression was 100% (range, 10% to 100%). A comparison of maximal and secondary CAIX staining intensity is shown in Table 1. Among the 708 CAIX-positive ccRCC tumors, 313 (44.2%) had the same maximal and secondary intensity, indicating homogenous CAIX staining within the entire section. The remaining 395 specimens (55.8%) had heterogeneous staining. For example, 55 specimens (7.8%) had marked maximal intensity, but weak intensity in at least 25% of the section.
There were 163 tumors (22.3%) with low CAIX expression and 567 tumors (77.7%) with high expression. Comparisons of clinical and pathologic features by CAIX expression are summarized in Table 2. Low CAIX expression was associated with symptoms at presentation, advanced nuclear grade, coagulative tumor necrosis, and sarcomatoid differentiation. For example 68.1% of tumors with low CAIX expression were grade 3 or 4 compared with 41.8% of tumors with high CAIX expression (P < .001).
Univariately, patients whose tumors contained low levels of CAIX expression were 65% more likely to die as a result of RCC compared with patients whose tumors contained high levels of CAIX expression (risk ratio = 1.65; 95% CI, 1.25 to 2.18; P < .001; Fig 2). Maximal CAIX intensity (log-rank P = .402) and heterogeneous CAIX intensity (log-rank P = .763) were not significantly associated with cancer-specific survival.
Associations of CAIX expression with death resulting from RCC adjusted for each clinical and pathologic feature are summarized in Table 3. After adjusting for either nuclear grade or tumor necrosis, low CAIX expression was no longer significantly associated with death from RCC (risk ratios = 1.17 [P = .279] and 1.24 [P = .138], respectively). After simultaneous adjustment for the TNM stage groupings, nuclear grade, and ECOG performance status, low CAIX expression was associated with a 14% increase in the risk of death resulting from RCC, but this difference was not statistically significant (risk ratio = 1.14; 95% CI, 0.85 to 1.52; P = .381). Lastly, CAIX expression was not significantly associated with death from RCC after adjusting for the SSIGN score (risk ratio = 1.24; 95% CI, 0.94 to 1.64; P = .134).
CAIX Expression in 81 Patients With Metastatic ccRCC Eighty-one patients had metastatic ccRCC at surgery, of whom 75 died from RCC at a median of 1.2 years (range, 0.1 to 14.0 years). In this subset, there were 24 tumors (29.6%) with low CAIX expression and 57 tumors (70.4%) with high CAIX expression. Low CAIX expression was not significantly associated with death from RCC for patients with metastatic disease either univariately (risk ratio = 1.32; 95% CI, 0.80 to 2.18; P = .281) or after adjusting for nuclear grade and ECOG performance status (risk ratio = 1.03; 95% CI, 0.61 to 1.73; P = .921).
CAIX Expression in Normal Tissues
We report the most extensive investigation to date to our knowledge of CAIX expression in a consecutive series of RCC tumors. Using the same anti-CAIX monoclonal antibody (clone M75) employed in previous studies, we confirm that CAIX expression varies among RCC histologic subtypes. Specifically, 97% of ccRCC tumors express CAIX, whereas fewer than 25% of papillary and chromophobe tumors express this protein. Among the subset of 730 ccRCC cases, 22% exhibited low levels of CAIX expression, which correlated univariately with an increased risk of death from RCC. However, contrary to previous reports,9,18 we demonstrate that low CAIX expression fails to predict an increased risk of death from RCC after adjusting for readily assessable pathologic features including nuclear grade and coagulative tumor necrosis. Additionally, we show that CAIX expression is heterogeneous within whole tumor specimens and further confirm that CAIX is expressed in multiple normal extrarenal tissues. The precise function of CAIX in normal and cancerous tissues remains unclear. Ivanov et al22 previously employed Northern blot analysis and immunohistochemistry to demonstrate CAIX expression within a variety of cell lines as well as normal and malignant human tissues. Specifically, CAIX was shown to be expressed by cancer cell lines derived from non–small-cell lung carcinoma, hematologic malignancies, and cancers of the colon, CNS, cervix, ovary, and prostate.22 Furthermore, CAIX was shown to be induced by hypoxic conditions, leading these investigators to postulate that CAIX functions to maintain an acidic microenvironment that promotes malignant progression.22 Consistent with our current findings, Ivanov et al also observed expression of CAIX within normal human mesothelium, gastric and small intestinal mucosa, biliary and gall bladder epithelium, testis, ovary, hair follicles, and choroid plexus.22 In separate studies, CAIX has been demonstrated to be constitutively expressed in RCC cell lines consequent to mutation of the von Hippel-Lindau protein,23 and CAIX has been implicated in regulation of cell adhesion and contact inhibition.24,25 Given that CAIX expression is a common feature within many forms of human cancer,22,26-28 it remains unclear whether CAIX plays a driving role in oncogenesis and progression, or rather, represents a general epiphenomenon of neoplastic dysregulation. Molecular markers lend the potential to (1) predict patient outcome and treatment responses; (2) identify high-risk patients who might benefit from aggressive adjunctive therapy; and (3) ideally, serve as tumor-associated targets to improve therapy. Bui et al9 stained TMAs of 321 ccRCC patients treated by nephrectomy and concluded that low CAIX expression was associated with increased risk of death resulting from RCC. Among the 149 patients (46%) with metastases, the association between low CAIX expression and increased risk of death persisted after adjusting for primary tumor classification, Fuhrman grade, nodal status, and ECOG performance status.9 In contrast, CAIX expression in the 172 nonmetastatic patients (54%) failed to act as an independent predictor of outcome.9 In a subsequent TMA study involving 224 ccRCC specimens, the same group reported that high Ki-67 (a nuclear protein that accompanies active cellular proliferation) combined with low CAIX expression predicted poorer rates of RCC-specific survival, even after multivariate adjustment.18 In contrast, our investigation of 730 ccRCC specimens reveals that low CAIX expression levels do not independently predict a higher risk of cancer death after multivariate adjustment for prognostic features as defined by either the University of California, Los Angeles, Integrated Staging System29 or the Mayo Clinic SSIGN3 scoring criteria. In fact, we demonstrate that there is no significant association between ccRCC CAIX expression and patient outcome when adjusted for a single prognostic factor, specifically, nuclear grade. Furthermore, we show that adjusting for another known prognostic feature, coagulative tumor necrosis,21,30,31 also negates any association between CAIX staining and patient outcome; a feature that was not considered in prior CAIX studies. There are distinct differences between the patient cohort studied at our institution and the patient cohorts reported in prior investigations of CAIX. Specifically, 11% of patients in our study presented with metastatic disease, with only 6% receiving high-dose IL-2. In contrast, 46% of patients reported by Bui et al9 presented with metastatic disease, and 60% of these patients received IL-2. In our current study, no association between CAIX and cancer-specific death in the subset of patients with metastatic disease was observed, even in a univariate setting. The disparity in observations made by our group and those reported by Bui et al9 raises the possibility that CAIX is predictive of favorable outcomes for patients with metastatic disease who receive IL-2–based immunotherapy. Additionally, our findings may differ from those previously reported, in part, because of the increased number of specimens examined and the consecutive-series nature of our study. Furthermore, the bulk of literature advocating CAIX as a predictive marker of RCC has been compiled using TMAs in lieu of whole-tumor tissue sections. Our study reveals significant heterogeneity of CAIX within whole tissue sections. Therefore, analyses using small tissue cores in a TMA may prove unreliable for assessing CAIX expression within RCC tumor specimens. This is particularly important given that TMAs are aggressively being exploited to survey CAIX expression (and other potential prognostic markers) to develop algorithms to predict responses to therapy, as has recently been reported for systemic IL-2.10 The findings of the current study do not necessarily preclude further exploitation of CAIX for the management of RCC. CAIX is being investigated as a therapeutic target for patients with RCC as well as a potential tumor-associated antigen to facilitate radioimmune imaging.12,17,32-39 Yet, CAIX-based imaging has yielded minimal sensitivity for detection of metastatic ccRCC.35 However, the potential utility for CAIX-based imaging to identify patients with clear cell histology, along with patients likely to respond to IL-2 immunotherapy or, conceivably, vascular endothelial growth factor–targeted therapies needs further investigation. Multiple phase I and II trials have indicated that anti-CAIX therapy is associated with infrequent and modest antitumoral responses with the highest response rates (23%) achieved only when used in combination with low-dose IL-2 therapy.12,17,32-34,36,37 Unquestionably, targeting CAIX for therapy is attractive because it is highly expressed by ccRCC. To date, clinical trials of CAIX-targeted therapy have not caused any significant toxicity.12,17,32-34,36,37 Given that CAIX is expressed in multiple normal human organs and tissues, however, expectations of anti-CAIX based therapy may need to be tempered. Specifically, it may prove difficult to evoke clinically meaningful RCC tumor regression while maintaining a low toxicity profile, especially if the antibodies tested in the clinical setting recognize the same epitope as the M75 antibody used to survey CAIX expression in RCC tissues and normal organs. More importantly, use of CAIX as an independent prognostic marker needs to be scrutinized before further clinical exploitation. At present, the utility of renal mass biopsy is constrained because of poor accuracy and high interobserver variability when reviewing small fragments of tumors.40,41 Our study demonstrates that patients with greater than 30% CAIX expression within their renal tumors harbor ccRCC, rather than papillary or chromophobe RCC. As such, CAIX may prove to increase the utility of renal mass biopsy to render an accurate diagnosis.8 Likewise, CAIX staining of biopsy tissues to diagnose ccRCC may facilitate proper assignment of systemic treatment to patients with advanced malignancy, or proper diagnosis for clinical trial accrual when subtype represents an eligibility criterion. In summary, we report the largest consecutive series survey of CAIX expression in RCC to date to our knowledge. High levels of CAIX expression are apparent in ccRCC tumors, whereas minimal expression is observed in papillary and chromophobe RCC. Low levels of CAIX expression are univariately associated with death from RCC, but this association is attenuated after adjustment for even a single prognostic feature such as nuclear grade or coagulative tumor necrosis. As such, CAIX assessment provides no added prognostic value to existing scoring algorithms. The high levels of CAIX expression within multiple normal tissues raises the question as to how CAIX-directed therapeutic toxicity will be kept to a minimum while facilitating a maximal antitumoral response. The ubiquitous nature of CAIX staining in ccRCC, although not useful as a prognostic marker, may gain utility as a diagnostic marker to increase the accuracy of pathologic interpretation of biopsy specimens.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: N/A Research Funds: N/A Testimony: N/A Other: Some of the authors have filed patient applications pertaining to other cancer prognostic markers, including B7 H1, B7 H3, B7 H4, and survivin.
Conception and design: Bradley C. Leibovich, Eugene D. Kwon Financial support: Eugene D. Kwon Administrative support: Bradley C. Leibovich, Christine M. Lohse, Eugene D. Kwon Provision of study materials or patients: Bradley C. Leibovich, John C. Cheville, Jan Zavada Collection and assembly of data: Yuri Sheinin, Christine M. Lohse, John C. Cheville Data analysis and interpretation: Bradley C. Leibovich, Yuri Sheinin, Christine M. Lohse, R. Houston Thompson, John C. Cheville, Eugene D. Kwon Manuscript writing: Bradley C. Leibovich, Christine M. Lohse, Robert Houston Thompson, John C. Cheville, Eugene D. Kwon Final approval of manuscript: Bradley C. Leibovich
We thank Catherine Lehman, RN, for help with data abstraction and patient follow-up.
Supported in part by the Richard M. Schulze Family Foundation, the Commonwealth Foundation for Cancer Research, and the Helen and Martin Kimmel Foundation. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 tests. Kaplan-Meier curves were used to visualize the association of CAIX expression with cancer-specific survival. Associations of CAIX expression with death from RCC were first evaluated in univariate Cox proportional hazards regression models and then in a multivariate setting adjusting for each clinical and pathologic feature. These associations were also evaluated after simultaneous adjustment for the TNM stage groupings, nuclear grade, and ECOG performance status, and after adjustment for the Mayo Clinic SSIGN score, a composite scoring system developed specifically for patients with ccRCC that includes primary tumor classification, regional lymph node involvement, distant metastases, tumor size, nuclear grade, and tumor necrosis.
