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Impact of Rhabdoid Differentiation on Prognosis for Patients with Grade 4 Renal Cell Carcinoma
EUROPEAN UROLOGY 68 (2015) 5–7
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Brief Correspondence
Impact of Rhabdoid Differentiation on Prognosis for Patients with Grade 4 Renal Cell Carcinoma Ben Y. Zhang a, John C. Cheville b, R. Houston Thompson c, Christine M. Lohse d, Stephen A. Boorjian c, Bradley C. Leibovich c, Brian A. Costello a,* a
Department of Oncology, Mayo Clinic, Rochester, MN, USA; b Department of Pathology, Mayo Clinic, Rochester, MN, USA; c Department of Urology,
Mayo Clinic, Rochester, MN, USA; d Division of Biomedical Informatics and Statistics, Mayo Clinic, Rochester, MN, USA
Article info
Abstract
Article history: Accepted January 1, 2015
Renal cell carcinoma (RCC) with rhabdoid differentiation is thought to portend a poor prognosis, similar to RCC with sarcomatoid differentiation. Both features are currently classified as grade 4 RCC based on the most recent International Society of Urological Pathology (ISUP) grading system. We reviewed a large series of patients with grade 4 RCC to determine the differential effects of rhabdoid and sarcomatoid differentiation on patient outcome. We identified 406 patients with ISUP grade 4 RCC including 111 (27%) with rhabdoid differentiation. In multivariable analysis of grade 4 RCC tumors, the presence of rhabdoid differentiation was not associated with death from RCC (hazard ratio [HR]: 0.95; p = 0.75); in contrast, sarcomatoid differentiation was significantly associated with death from RCC (HR: 1.63; p < 0.001). Patients with RCC with rhabdoid differentiation were significantly more likely to die of RCC than a comparison cohort of 1758 patients with grade 3 RCC (HR: 2.45; p < 0.001). The novel findings of our study suggest that rhabdoid and sarcomatoid differentiation should not be grouped together when assessing risk in a patient with grade 4 RCC but support the notion that rhabdoid differentiation is appropriately placed in the ISUP grade 4 category. # 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Keywords: Renal cell carcinoma Rhabdoid differentiation Prognosis Survival Sarcomatoid differentiation
* Corresponding author. Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel. +1 507 284 4320. E-mail address: [email protected] (B.A. Costello).
Renal cell carcinoma (RCC) with rhabdoid differentiation is a rare but aggressive pattern of differentiation that is present in approximately 5% of all patients with RCC [1], and it can occur in association with any histologic subtype [2]. It is characterized by cells with abundant eosinophilic cytoplasm and large eccentric nuclei with prominent nucleoli that resemble rhabdomyoblasts (Fig. 1). At our institution, all RCCs with rhabdoid differentiation are classified as grade 4 in accordance with the International Society of Urological Pathology (ISUP) grading system [2]. Based on the results of prior small case series, this subset of RCCs was thought to portend a poor prognosis similar to sarcomatoid differentiation [1,3]. Although the most recent ISUP grading system classifies RCCs with either
rhabdoid or sarcomatoid differentiation as grade 4, it remains unclear if RCC with rhabdoid differentiation has a prognosis similar to sarcomatoid RCC or nonsarcomatoid grade 4 RCC [2]. We reviewed a large series of patients with grade 4 RCC to determine the differential effects of rhabdoid and sarcomatoid differentiation on patient outcome. Full study methods are described in Supplement 1. Using the Mayo Clinic Nephrectomy Registry, we identified 406 patients with ISUP grade 4 RCC and 1758 patients with grade 3 RCC. Initial clinical and pathologic features were documented, and patient outcomes were routinely updated. To obtain the pathologic features, a urologic pathologist (J.C.C.) reviewed the microscopic slides from all specimens without knowledge of patient outcome. Associations of
http://dx.doi.org/10.1016/j.eururo.2015.01.002 0302-2838/# 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
6
EUROPEAN UROLOGY 68 (2015) 5–7
[(Fig._1)TD$IG]
Fig. 1 – Rhabdoid differentiation characterized by large epithelioid cells with eosinophilic paranuclear intracytoplasmic inclusions and large eccentric nuclei with prominent nucleoli that resemble rhabdomyoblasts.
clinical and pathologic features with death from RCC were evaluated using Cox proportional hazards regression models and summarized with hazard ratios (HRs) and 95% confidence intervals (CIs). Supplementary Table 1 summarizes the clinical and pathologic features for the 406 patients with grade 4 RCC under study by rhabdoid differentiation. Univariable and multivariable associations of clinical and pathologic features with death from RCC are summarized in Supplementary Table 2, and cancer-specific survival for patients whose tumors did and did not contain rhabdoid differentiation is illustrated in Supplementary Figure 1. After adjusting for age, the primary tumor, regional lymph node and distant metastases classifications, coagulative tumor necrosis, and sarcomatoid differentiation, the HR for the association of rhabdoid differentiation with death from RCC was 0.95 (95% [(Fig._2)TD$IG]CI, 0.71–1.28; p = 0.75).
To further investigate the disparate effects of rhabdoid and sarcomatoid differentiation on patient outcome, the 406 grade 4 tumors studied were separated into 83 (20%) with rhabdoid differentiation only, 161 (40%) with sarcomatoid differentiation only, 28 (7%) with both, and 134 (33%) with neither. Cancer-specific survival for these groups is illustrated in Figure 2. Treating tumors with neither rhabdoid nor sarcomatoid differentiation as the reference, the HRs for the associations of rhabdoid only, sarcomatoid only, and both rhabdoid and sarcomatoid with death from RCC were 1.03 (95% CI, 0.72–1.46; p = 0.88), 2.04 (95% CI, 1.52–2.72; p < 0.001), and 1.47 (95% CI, 0.87–2.47; p = 0.15), respectively. To confirm that rhabdoid differentiation is appropriately placed in the ISUP grade 4 category, cancer-specific survival for the 83 patients whose tumors demonstrated rhabdoid differentiation only was also compared with 1758 patients treated surgically for ISUP grade 3 tumors during the same time frame including 833 grade 3 tumors that contained coagulative tumor necrosis. Patients with grade 4 tumors that contained rhabdoid differentiation only were significantly more likely to die from RCC compared with all patients with grade 3 tumors (HR: 2.45; 95% CI, 1.86–3.23; p < 0.001) and necrotic grade 3 tumors (HR: 1.62; 95% CI, 1.22–2.14; p < 0.001). There are currently slightly >100 reported cases of RCC with rhabdoid differentiation in the literature. An early comprehensive series of 480 RCC patients, including 23 with rhabdoid differentiation, by Gokden et al revealed that RCC with rhabdoid differentiation was related to higher clinical stage and Fuhrman grade [1]. A recent series by Przybycin et al of 49 patients with clear cell RCC with rhabdoid differentiation demonstrated that rhabdoid differentiation in RCC conferred an increased risk of death, independent of other prognostic factors (HR: 5.25; p < 0.001) [4]. The comparison cohort consisted of 31 patients with ISUP grade 3 tumors and only 10 patients with ISUP grade 4 tumors. Because RCC with rhabdoid
100
Cancer-specific survival, %
80
Grade 3 60
Neither
40
Rhabdoid only 20
Both Sarcomatoid only
0 0
2
4
6
8
10
Years Fig. 2 – Cancer-specific survival for patients with grade 4 renal cell carcinomas (RCCs) with both rhabdoid and sarcomatoid differentiation, rhabdoid differentiation only, sarcomatoid differentiation only, or neither rhabdoid nor sarcomatoid differentiation. The survival curve for patients with grade 3 RCCs is included for comparison.
EUROPEAN UROLOGY 68 (2015) 5–7
differentiation is classified as grade 4 per the most recent ISUP grading system, the large proportion of ISUP grade 3 tumors in the comparison group likely had an impact on the results of their survival analysis. In addition, 76% of patients in the rhabdoid group had stage T3a or higher advanced tumors compared with only 37% in the nonrhabdoid group, so differences in outcome may have been affected not only by the presence of rhabdoid differentiation but also a striking difference in stage. We report the largest study to date with 111 patients and demonstrate that the presence of rhabdoid differentiation does not confer an increased risk of death for patients with grade 4 RCC. In our multivariable analysis, there was not a statistically significant association between the presence of rhabdoid differentiation and death from RCC (HR: 0.95; p = 0.75); sarcomatoid differentiation was shown to be a statistically significant prognostic feature after multivariable adjustment (HR: 1.63; p < 0.001), consistent with the results of prior studies on sarcomatoid differentiation [5–9]. Strengths of this study include the large sample size, uniform pathologic re-review, and long-term follow-up. Our study also has a few limitations including its retrospective design, single-center experience, and large portion of cases outside of the targeted therapy era. In summary, the novel findings of our study suggest that rhabdoid and sarcomatoid differentiation should not be grouped together when assessing risk in a patient with grade 4 RCC. Because patients with RCC with rhabdoid differentiation only had similar clinical outcomes compared with those with grade 4 RCC without rhabdoid or sarcomatoid differentiation and yet demonstrated significantly poorer outcomes compared with patients with grade 3 tumors, our results support the most recent ISUP grading system classifying any tumor with rhabdoid differentiation as grade 4. We believe our results may have a significant impact on the future assessment of rhabdoid features in the ISUP grading system. Author contributions: Brian A. Costello had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Zhang, Cheville, Costello. Acquisition of data: Lohse. Analysis and interpretation of data: Zhang, Lohse, Cheville. Drafting of the manuscript: Zhang, Lohse. Critical revision of the manuscript for important intellectual content:
7
Obtaining funding: None. Administrative, technical, or material support: Zhang. Supervision: Costello, Thompson, Cheville. Other (specify): None. Financial disclosures: Brian A. Costello certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. eururo.2015.01.002. References [1] Gokden N, Nappi O, Swanson PE, et al. Renal cell carcinoma with rhabdoid features. Am J Surg Pathol 2000;24:1329–38. [2] Delahunt B, Cheville JC, Martignoni G, et al. The International Society of Urological Pathology (ISUP) grading system for renal cell carcinoma and other prognostic parameters. Am J Surg Pathol 2013;37:1490–504. [3] Kuroiwa K, Kinoshita Y, Shiratsuchi H, et al. Renal cell carcinoma with rhabdoid features: an aggressive neoplasm. Histopathology 2002;41: 538–48. [4] Przybycin CG, McKenney JK, Reynolds JP, et al. Rhabdoid differentiation is associated with aggressive behavior in renal cell carcinoma: a clinicopathologic analysis of 76 cases with clinical follow-up. Am J Surg Pathol 2014;38:1260–5. [5] Zhang BY, Thompson RH, Lohse CM, et al. A novel prognostic model for patients with sarcomatoid renal cell carcinoma. BJU Int 2015; 115:405–11. [6] Cheville JC, Lohse CM, Zincke H, et al. Sarcomatoid renal cell carcinoma: an examination of underlying histologic subtype and an analysis of associations with patient outcome. Am J Surg Pathol 2004;28:435–41. [7] Mian BM, Bhadkamkar N, Slaton JW, et al. Prognostic factors and survival of patients with sarcomatoid renal cell carcinoma. J Urol 2002; 167:65–70. [8] de Peralta-Venturina M, Moch H, Amin M, et al. Sarcomatoid differentiation in renal cell carcinoma: a study of 101 cases. Am J Surg Pathol 2001;25:275–84. [9] Shuch B, Bratslavsky G, Shih J, et al. Impact of pathological tumour
Cheville, Lohse, Boorjian, Thompson, Leibovich, Costello.
characteristics in patients with sarcomatoid renal cell carcinoma.
Statistical analysis: Lohse.
BJU Int 2012;109:1600–6.
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Brief Correspondence
Impact of Rhabdoid Differentiation on Prognosis for Patients with Grade 4 Renal Cell Carcinoma Ben Y. Zhang a, John C. Cheville b, R. Houston Thompson c, Christine M. Lohse d, Stephen A. Boorjian c, Bradley C. Leibovich c, Brian A. Costello a,* a
Department of Oncology, Mayo Clinic, Rochester, MN, USA; b Department of Pathology, Mayo Clinic, Rochester, MN, USA; c Department of Urology,
Mayo Clinic, Rochester, MN, USA; d Division of Biomedical Informatics and Statistics, Mayo Clinic, Rochester, MN, USA
Article info
Abstract
Article history: Accepted January 1, 2015
Renal cell carcinoma (RCC) with rhabdoid differentiation is thought to portend a poor prognosis, similar to RCC with sarcomatoid differentiation. Both features are currently classified as grade 4 RCC based on the most recent International Society of Urological Pathology (ISUP) grading system. We reviewed a large series of patients with grade 4 RCC to determine the differential effects of rhabdoid and sarcomatoid differentiation on patient outcome. We identified 406 patients with ISUP grade 4 RCC including 111 (27%) with rhabdoid differentiation. In multivariable analysis of grade 4 RCC tumors, the presence of rhabdoid differentiation was not associated with death from RCC (hazard ratio [HR]: 0.95; p = 0.75); in contrast, sarcomatoid differentiation was significantly associated with death from RCC (HR: 1.63; p < 0.001). Patients with RCC with rhabdoid differentiation were significantly more likely to die of RCC than a comparison cohort of 1758 patients with grade 3 RCC (HR: 2.45; p < 0.001). The novel findings of our study suggest that rhabdoid and sarcomatoid differentiation should not be grouped together when assessing risk in a patient with grade 4 RCC but support the notion that rhabdoid differentiation is appropriately placed in the ISUP grade 4 category. # 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Keywords: Renal cell carcinoma Rhabdoid differentiation Prognosis Survival Sarcomatoid differentiation
* Corresponding author. Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel. +1 507 284 4320. E-mail address: [email protected] (B.A. Costello).
Renal cell carcinoma (RCC) with rhabdoid differentiation is a rare but aggressive pattern of differentiation that is present in approximately 5% of all patients with RCC [1], and it can occur in association with any histologic subtype [2]. It is characterized by cells with abundant eosinophilic cytoplasm and large eccentric nuclei with prominent nucleoli that resemble rhabdomyoblasts (Fig. 1). At our institution, all RCCs with rhabdoid differentiation are classified as grade 4 in accordance with the International Society of Urological Pathology (ISUP) grading system [2]. Based on the results of prior small case series, this subset of RCCs was thought to portend a poor prognosis similar to sarcomatoid differentiation [1,3]. Although the most recent ISUP grading system classifies RCCs with either
rhabdoid or sarcomatoid differentiation as grade 4, it remains unclear if RCC with rhabdoid differentiation has a prognosis similar to sarcomatoid RCC or nonsarcomatoid grade 4 RCC [2]. We reviewed a large series of patients with grade 4 RCC to determine the differential effects of rhabdoid and sarcomatoid differentiation on patient outcome. Full study methods are described in Supplement 1. Using the Mayo Clinic Nephrectomy Registry, we identified 406 patients with ISUP grade 4 RCC and 1758 patients with grade 3 RCC. Initial clinical and pathologic features were documented, and patient outcomes were routinely updated. To obtain the pathologic features, a urologic pathologist (J.C.C.) reviewed the microscopic slides from all specimens without knowledge of patient outcome. Associations of
http://dx.doi.org/10.1016/j.eururo.2015.01.002 0302-2838/# 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
6
EUROPEAN UROLOGY 68 (2015) 5–7
[(Fig._1)TD$IG]
Fig. 1 – Rhabdoid differentiation characterized by large epithelioid cells with eosinophilic paranuclear intracytoplasmic inclusions and large eccentric nuclei with prominent nucleoli that resemble rhabdomyoblasts.
clinical and pathologic features with death from RCC were evaluated using Cox proportional hazards regression models and summarized with hazard ratios (HRs) and 95% confidence intervals (CIs). Supplementary Table 1 summarizes the clinical and pathologic features for the 406 patients with grade 4 RCC under study by rhabdoid differentiation. Univariable and multivariable associations of clinical and pathologic features with death from RCC are summarized in Supplementary Table 2, and cancer-specific survival for patients whose tumors did and did not contain rhabdoid differentiation is illustrated in Supplementary Figure 1. After adjusting for age, the primary tumor, regional lymph node and distant metastases classifications, coagulative tumor necrosis, and sarcomatoid differentiation, the HR for the association of rhabdoid differentiation with death from RCC was 0.95 (95% [(Fig._2)TD$IG]CI, 0.71–1.28; p = 0.75).
To further investigate the disparate effects of rhabdoid and sarcomatoid differentiation on patient outcome, the 406 grade 4 tumors studied were separated into 83 (20%) with rhabdoid differentiation only, 161 (40%) with sarcomatoid differentiation only, 28 (7%) with both, and 134 (33%) with neither. Cancer-specific survival for these groups is illustrated in Figure 2. Treating tumors with neither rhabdoid nor sarcomatoid differentiation as the reference, the HRs for the associations of rhabdoid only, sarcomatoid only, and both rhabdoid and sarcomatoid with death from RCC were 1.03 (95% CI, 0.72–1.46; p = 0.88), 2.04 (95% CI, 1.52–2.72; p < 0.001), and 1.47 (95% CI, 0.87–2.47; p = 0.15), respectively. To confirm that rhabdoid differentiation is appropriately placed in the ISUP grade 4 category, cancer-specific survival for the 83 patients whose tumors demonstrated rhabdoid differentiation only was also compared with 1758 patients treated surgically for ISUP grade 3 tumors during the same time frame including 833 grade 3 tumors that contained coagulative tumor necrosis. Patients with grade 4 tumors that contained rhabdoid differentiation only were significantly more likely to die from RCC compared with all patients with grade 3 tumors (HR: 2.45; 95% CI, 1.86–3.23; p < 0.001) and necrotic grade 3 tumors (HR: 1.62; 95% CI, 1.22–2.14; p < 0.001). There are currently slightly >100 reported cases of RCC with rhabdoid differentiation in the literature. An early comprehensive series of 480 RCC patients, including 23 with rhabdoid differentiation, by Gokden et al revealed that RCC with rhabdoid differentiation was related to higher clinical stage and Fuhrman grade [1]. A recent series by Przybycin et al of 49 patients with clear cell RCC with rhabdoid differentiation demonstrated that rhabdoid differentiation in RCC conferred an increased risk of death, independent of other prognostic factors (HR: 5.25; p < 0.001) [4]. The comparison cohort consisted of 31 patients with ISUP grade 3 tumors and only 10 patients with ISUP grade 4 tumors. Because RCC with rhabdoid
100
Cancer-specific survival, %
80
Grade 3 60
Neither
40
Rhabdoid only 20
Both Sarcomatoid only
0 0
2
4
6
8
10
Years Fig. 2 – Cancer-specific survival for patients with grade 4 renal cell carcinomas (RCCs) with both rhabdoid and sarcomatoid differentiation, rhabdoid differentiation only, sarcomatoid differentiation only, or neither rhabdoid nor sarcomatoid differentiation. The survival curve for patients with grade 3 RCCs is included for comparison.
EUROPEAN UROLOGY 68 (2015) 5–7
differentiation is classified as grade 4 per the most recent ISUP grading system, the large proportion of ISUP grade 3 tumors in the comparison group likely had an impact on the results of their survival analysis. In addition, 76% of patients in the rhabdoid group had stage T3a or higher advanced tumors compared with only 37% in the nonrhabdoid group, so differences in outcome may have been affected not only by the presence of rhabdoid differentiation but also a striking difference in stage. We report the largest study to date with 111 patients and demonstrate that the presence of rhabdoid differentiation does not confer an increased risk of death for patients with grade 4 RCC. In our multivariable analysis, there was not a statistically significant association between the presence of rhabdoid differentiation and death from RCC (HR: 0.95; p = 0.75); sarcomatoid differentiation was shown to be a statistically significant prognostic feature after multivariable adjustment (HR: 1.63; p < 0.001), consistent with the results of prior studies on sarcomatoid differentiation [5–9]. Strengths of this study include the large sample size, uniform pathologic re-review, and long-term follow-up. Our study also has a few limitations including its retrospective design, single-center experience, and large portion of cases outside of the targeted therapy era. In summary, the novel findings of our study suggest that rhabdoid and sarcomatoid differentiation should not be grouped together when assessing risk in a patient with grade 4 RCC. Because patients with RCC with rhabdoid differentiation only had similar clinical outcomes compared with those with grade 4 RCC without rhabdoid or sarcomatoid differentiation and yet demonstrated significantly poorer outcomes compared with patients with grade 3 tumors, our results support the most recent ISUP grading system classifying any tumor with rhabdoid differentiation as grade 4. We believe our results may have a significant impact on the future assessment of rhabdoid features in the ISUP grading system. Author contributions: Brian A. Costello had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Zhang, Cheville, Costello. Acquisition of data: Lohse. Analysis and interpretation of data: Zhang, Lohse, Cheville. Drafting of the manuscript: Zhang, Lohse. Critical revision of the manuscript for important intellectual content:
7
Obtaining funding: None. Administrative, technical, or material support: Zhang. Supervision: Costello, Thompson, Cheville. Other (specify): None. Financial disclosures: Brian A. Costello certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. eururo.2015.01.002. References [1] Gokden N, Nappi O, Swanson PE, et al. Renal cell carcinoma with rhabdoid features. Am J Surg Pathol 2000;24:1329–38. [2] Delahunt B, Cheville JC, Martignoni G, et al. The International Society of Urological Pathology (ISUP) grading system for renal cell carcinoma and other prognostic parameters. Am J Surg Pathol 2013;37:1490–504. [3] Kuroiwa K, Kinoshita Y, Shiratsuchi H, et al. Renal cell carcinoma with rhabdoid features: an aggressive neoplasm. Histopathology 2002;41: 538–48. [4] Przybycin CG, McKenney JK, Reynolds JP, et al. Rhabdoid differentiation is associated with aggressive behavior in renal cell carcinoma: a clinicopathologic analysis of 76 cases with clinical follow-up. Am J Surg Pathol 2014;38:1260–5. [5] Zhang BY, Thompson RH, Lohse CM, et al. A novel prognostic model for patients with sarcomatoid renal cell carcinoma. BJU Int 2015; 115:405–11. [6] Cheville JC, Lohse CM, Zincke H, et al. Sarcomatoid renal cell carcinoma: an examination of underlying histologic subtype and an analysis of associations with patient outcome. Am J Surg Pathol 2004;28:435–41. [7] Mian BM, Bhadkamkar N, Slaton JW, et al. Prognostic factors and survival of patients with sarcomatoid renal cell carcinoma. J Urol 2002; 167:65–70. [8] de Peralta-Venturina M, Moch H, Amin M, et al. Sarcomatoid differentiation in renal cell carcinoma: a study of 101 cases. Am J Surg Pathol 2001;25:275–84. [9] Shuch B, Bratslavsky G, Shih J, et al. Impact of pathological tumour
Cheville, Lohse, Boorjian, Thompson, Leibovich, Costello.
characteristics in patients with sarcomatoid renal cell carcinoma.
Statistical analysis: Lohse.
BJU Int 2012;109:1600–6.