- Email: [email protected]
Sarcomatoid Renal Cell Carcinoma: Population-Based Study of 879 Patients
Original Study
Sarcomatoid Renal Cell Carcinoma: Population-Based Study of 879 Patients Michail Alevizakos,1 Apostolos Gaitanidis,2 Dimitrios Nasioudis,3 Pavlos Msaouel,4 Leonard J. Appleman5 Abstract Sarcomatoid renal cell carcinoma constitutes a rare and aggressive subtype of renal cell carcinoma. Among a recent multi-institutional cohort of 879 patients, the majority present with metastatic disease, and overall prognosis is poor; older age and higher disease stage were associated with poorer disease-specific survival (DSS). Notably, performance of nephrectomy was associated with improved DSS independent of disease stage. Background: Sarcomatoid renal cell carcinoma (sRCC) constitutes a rare and aggressive subtype of renal cell carcinoma. We aimed to investigate its clinicopathologic characteristics and outcomes at a national level. Patients and Methods: We accessed the National Cancer Institute’s Surveillance, Epidemiology, and End Results database (2010-2015) and extracted data on patients with sRCC. We estimated median, 1-, 3-, and 5-year disease-specific survival (DSS) probabilities after generation of Kaplan-Meier curves and used multivariable regression to evaluate variables associated with nephrectomy and DSS. Results: A total of 879 patients with sRCC were identified; 60.9% patients had stage IV disease at diagnosis, and the median tumor size was 8.3 cm (interquartile range, 5.5-12 cm). The 5-year DSS were 77.7%, 67.8%, 35.4%, and 3.5% for patients with stage I, II, III, and IV disease at diagnosis, respectively; median DSS was 9 months (interquartile range, 4-42 months) for the entire cohort. Older age (hazard ratio [HR] ¼ 1.01; 95% confidence interval [CI], 1.00-1.02), higher tumor stage (stage III vs. I: HR ¼ 3.81; 95% CI, 2.18-6.67; stage IV vs. I: HR ¼ 9.89; 95% CI, 5.80-16.98), and performance of nephrectomy (HR ¼ 0.53; 95% CI, 0.43-0.66) were found to independently affect DSS. Conclusion: In the largest sRCC cohort to date, we found that most patients present with metastatic disease, and the prognosis for this disease remains extremely poor. Nephrectomy should be considered in all patients with acceptable surgical risk, including cytoreductive nephrectomy in carefully selected patients with metastatic disease. Clinical Genitourinary Cancer, Vol. 17, No. 3, e447-53 ª 2019 Elsevier Inc. All rights reserved. Keywords: Nephrectomy, Prognosis, SEER, SRCC, Survival
Introduction Renal cell carcinoma (RCC) with sarcomatoid dedifferentiation (sarcomatoid renal cell carcinoma, sRCC) constitutes a rare subgroup of RCC, accounting for approximately 5% to 7% of all RCC cases.1-3 It is not a distinct pathologic entity according to the 2016 1
Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA Second Department of Surgery, University General Hospital of Alexandroupoli, Democritus University of Thrace Medical School, Alexandroupoli, Greece 3 Department of Obstetrics and Gynecology, Hospital of the University of Pennsylvania, Philadelphia, PA 4 Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 5 Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, PA 2
Submitted: Nov 4, 2018; Revised: Dec 29, 2018; Accepted: Jan 8, 2019; Epub: Jan 17, 2019 Address for correspondence: Michail Alevizakos, MD, Department of Medicine, UPMC Montefiore Hospital, N-715, 200 Lothrop St, Pittsburgh, PA 15213 Fax: (412) 692-4944; e-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.clgc.2019.01.005
World Health Organization classification because the presence of sarcomatoid components constitutes a dedifferentiation that can occur in all types of RCC.4 Histologically, sRCC thus contains both epithelial (carcinomatous) and mesenchymal (sarcomatoid) components, unlike a true sarcoma of the kidney.5,6 However, it is frequently studied as a distinct clinical entity because it is associated with an aggressive phenotype, advanced stage at diagnosis, and worse overall survival (OS) and disease-specific survival (DSS).1,7 Additionally, it responds poorly to cytotoxic chemotherapy, cytokines, and targeted therapies.2,7,8 Notably, a higher percentage of sarcomatoid features is associated with worse survival.9,10 To delineate the clinicopathologic characteristics and outcomes of patients with sRCC at a national level, we queried the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database. This allowed us to more accurately define outcomes of this disease and their association with potential predictors at the national level.
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Sarcomatoid Renal Cell Carcinoma Table 1 Demographic and Clinical Characteristics of Patients With Sarcomatoid Renal Cell Carcinoma Total (N [ 879)
Nephrectomy Performeda (N [ 577)
Nephrectomy Not Performeda (N [ 295)
29 (10-44)
30 (14-46)
15 (5-35)
Male
613 (69.7%)
406 (70.4%)
203 (68.8%)
Female
266 (30.3%)
171 (29.6%)
92 (31.2%)
63.4 12.1
62 11.9
65.9 11.9
White
713 (81.1%)
465 (80.6%)
241 (81.7%)
Black
103 (11.7%)
65 (11.3%)
38 (12.9%)
56 (6.4%)
41 (7.1%)
15 (5.1%)
7 (0.8%)
6 (1%)
1 (0.3%) 167 (56.6%)
Characteristic Follow-up (mo), median (IQR) Gender
Age (y), mean SD Ethnicity
Other (American Indian, Alaska Native, Asian, Pacific Islander) Unknown Marital Status Married
524 (59.6%)
352 (61%)
Divorced, separated, or widowed
171 (19.5%)
100 (17.3%)
71 (24.1%)
Single or never married
139 (15.8%)
92 (16%)
45 (15.3%)
45 (5.1%)
33 (5.7%)
12 (4%)
Unknown Insurance Status Insured
831 (94.5%)
545 (94.4%)
279 (94.6%)
Not insured
27 (3.1%)
16 (2.8%)
11 (3.7%)
Unknown
21 (2.4%)
16 (2.8%)
5 (1.7%)
I
97 (11%)
91 (15.7%)
6 (2%)
II
30 (3.4%)
27 (4.7%)
III
196 (22.3%)
188 (32.6%)
8 (2.7%)
IV
535 (60.9%)
264 (45.8%)
267 (90.5%)
21 (2.4%)
7 (1.2%)
11 (3.8%)
Lung
305 (34.6%)
133 (23.1%)
170 (57.6%)
Bone
207 (23.5%)
78 (13.5%)
129 (43.7%)
Liver
111 (12.6%)
39 (6.8%)
72 (24.4%)
45 (5.1%)
14 (2.4%)
31 (10.5%)
Stage
Unknown
3 (1%)
Metastatic Disease
Brain Nephrectomy Performed Yes Radical nephrectomy
577 (65.6%) 425
Simple nephrectomy/nephroureterectomy
43
Partial nephrectomy
61
Nephrectomy NOS No Unknown
48 295 (33.6%) 7 (0.8%)
Abbreviations: IQR ¼ interquartile range; NOS ¼ not otherwise specified. a Performance of nephrectomy was not specified in 7 patients.
Patients and Methods A cohort of patients with sRCC was drawn from the SEER database, which incorporates high-quality data deriving from 18 cancer registries and covers approximately 34.6% of the total US population based on the 2010 census.11 All patient data are deidentified and available to the public for research purposes. As such, the SEER database permits the study of malignancies with an extremely low incidence. Because SEER contains only deidentified
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data, no institutional review board approval was required for the conduct of this study. The following criteria were applied to identify eligible cases of sRCC: microscopically confirmed tumor, ICD-O-3 histology codes 8318/3 (“Renal cell carcinoma, sarcomatoid”), tumor diagnosed between January 1, 2010, and December 31, 2015, active followup, and reported tumor being the primary lesion by the rules of the International Association of Cancer Registry.12 We selected the
Michail Alevizakos et al Table 2 Disease-Specific Survival Probabilities of Patients With Sarcomatoid Renal Cell Carcinoma by Disease Stage Stage Survival 1 year 3 year 5 year Survival (mo), median (IQR)
I
II
III
88% (78.1-93.6) 77.7% (66.6-86.1) 77.7% (65.6-86.1) Not reached
82.7% (60.1-93.2) 67.8% (43.7-83.3) 67.8% (43.7-83.3) Not reached
67% (58.5%-74.2%) 37.1% (28.1-46.2) 35.4% (26.2-44.6) 18 (8-not reached)
IV 23.8% 7% 3.5% 5
All Stages Combined
(19.5-28.3) (4.3-10.6) (1.4-7.3) (2-12)
43.7% 25.8% 23.5% 9
(39.7-49.5) (22.1-29.7) (19.7-27.6) (4-42)
Data in parentheses are 95% confidence interval unless otherwise indicated. Abbreviations: IQR ¼ interquartile range; NA ¼ not applicable.
aforementioned period of observation because it was the one containing data on site-specific synchronous metastases. We used the “case listing” option to extract demographic, clinicopathologic, and survival data. Specifically, we extracted information on patient gender, age at diagnosis, ethnicity, marital status, and insurance status. Additionally, we recorded tumor size and stage at diagnosis, the presence of synchronous bone, brain, lung, and liver metastases, and whether patients had undergone nephrectomy. Staging information was based on the derived 8th edition of the American Joint Committee on Cancer staging system.13 We also gathered data on recorded survival and cause of death for all patients. We generated Kaplan-Meier curves to determine median and 1-, 3-, and 5-year DSS probabilities.14 We used the reverse KaplanMeier method to calculate the median follow-up time. For DSS, only death attributable to sRCC was considered to be an event, and patients diagnosed with more than one primary tumor were excluded to prevent confounding.15 We used similar methodology to calculate OS, in which case death from any cause was considered an event. To avoid the inherent inferential limitations associated
with these approaches, we did not perform variable selection by univariate comparisons or stepwise procedures.16 We instead generated prespecified regression models with all covariates chosen on the basis of background knowledge and theoretical considerations.16 Accordingly, we performed multivariable Cox regression to identify the effect of age, ethnicity, insurance status, tumor stage, and performance of nephrectomy in DSS. We also performed a multivariable logistic regression to identify the effect of age, gender, ethnicity, marital status, insurance status, tumor stage, and presence of metastatic (M1) disease on whether nephrectomy was performed. Because sRCC is by definition grade 4,13 grade was not included in our analysis. Statistical analysis was performed by Stata 13 software package (StataCorp, College Station, TX), and the a level of statistical significance was set at 0.05.
Results Overall, we identified 879 patients with sRCC; median follow-up time was 29 months (interquartile range [IQR], 10-44 months). At diagnosis, 97 patients (11%) had stage I disease, 30 (3.4%) stage II
Disease-Specific Survival (%) 0.00 0.25 0.50 0.75 1.00
Figure 1 Kaplan-Meier Cancer-Specific Survival Curve of Patients With Sarcomatoid Renal Cell Carcinoma, Stratified by Stage at Diagnosis
Number at risk Stage = 1 Stage = 2 Stage = 3 Stage = 4
0
20
40 Months
60
80
79 27 157 431
52 14 53 35
24 4 24 6
10 0 7 3
0 0 0 0
Stage = 1 Stage = 3
Stage = 2 Stage = 4
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Sarcomatoid Renal Cell Carcinoma
0.00
Overall Survival (%) 0.25 0.50 0.75 1.00
Figure 2 Kaplan-Meier Overall Survival Curve of Patients With Sarcomatoid Renal Cell Carcinoma, Stratified by Stage at Diagnosis
Number at risk Stage = 1 Stage = 2 Stage = 3 Stage = 4
0
20
40 Months
60
80
79 27 157 431
52 14 53 35
24 4 24 6
10 0 7 3
0 0 0 0
Stage = 1 Stage = 3
disease, 196 (22.3%) stage III disease, and 535 (60.9%) stage IV disease; disease stage was unknown for 21 patients (2.4%). The median tumor size was 83 mm (IQR, 55-120 mm). The clinical and demographic characteristics of the studied cohort are listed in Table 1. In multivariable analysis, older age (odds ratio [OR] ¼ 0.96; 95% confidence interval [CI], 0.94-0.97), presence of M1 disease (OR ¼ 0.26; 95% CI, 0.12-0.53), and stage IV disease (OR ¼ 0.16; 95% CI, 0.05-0.52) were inversely and independently associated with performance of nephrectomy. Of the 879 available patients, data from 759 (86.3%) were utilized to calculate DSS and OS, as 120 patients (13.7%) had been diagnosed with more than one primary tumor. The 1-, 3-, and 5-year DSS probabilities for all patients were 43.7%, 25.8%, and 23.5%, respectively, and the median DSS for the entire cohort was 9 months (IQR, 4-42 months). Additionally, the 1-, 3-, and 5-year
Table 3 Disease-Specific Survival Probabilities of Patients With Stage IV Sarcomatoid Renal Cell Carcinoma According to Performance of Nephrectomy
Survival 1 year 3 year 5 year Survival (mo), median (IQR)
Stage IV Disease With Nephrectomy 33.7% 10.8% 6.2% 7
(26.7-39.5) (6.5-16.5) (2.5-12.3) (3-17)
Stage IV Disease Without Nephrectomy 11.5% 1.9% 0% 4
Data in parentheses are 95% confidence interval unless otherwise indicated. Abbreviations: IQR ¼ interquartile range; NA ¼ not applicable.
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(7-17.2) (0.4-5.9) (NA) (2-7)
Stage = 2 Stage = 4
OS probabilities for all patients were 41.9%, 22.9%, and 20.2%, respectively, and the median OS for the entire cohort was 8 months (IQR, 3-30 month). DSS probabilities by stage are provided in Table 2 and Figure 1, and OS probabilities by stage are depicted in Figure 2. Among 472 patients with stage IV disease, the 1-, 3-, and 5-year DSS probabilities for patients who underwent nephrectomy were 33.7%, 10.8%, and 6.2%, respectively, whereas the same DSS probabilities were 11.5%, 1.9%, and 0 for patients who did not undergo nephrectomy. Among these patients, median DSS was 7 months (IQR, 3-17 months) among patients who underwent nephrectomy versus 4 months (IQR, 2-7 months) for patients treated nonsurgically. DSS probabilities stratified by performance of nephrectomy for patients with stage IV disease are provided in Table 3 and Figure 3. In multivariable analysis, older age (hazard ratio [HR] ¼ 1.01; 95% CI, 1.00-1.02), higher tumor stage (stage III vs. I: HR ¼ 3.81; 95% CI, 2.18-6.67; stage IV vs. I: HR ¼ 9.89; 95% CI, 5.80-16.98), and performance of nephrectomy (HR ¼ 0.53; 95% CI, 0.43-0.66) were found to be significantly and independently associated with DSS (Table 4).
Discussion RCC with sarcomatoid dedifferentiation constitutes an aggressive subtype of RCC that portends a poor prognosis.1 In our study, which to our knowledge contains the largest contemporary studied cohort of sRCC patients, we explored the epidemiology of this tumor by utilizing recent aggregate data from a multi-institutional national registry. Importantly, we found that the majority of patients with sRCC present with large primary tumors as well as synchronous metastases, and patients overall have a poor median DSS of 9 months. We also identified that a higher tumor stage at
Michail Alevizakos et al
Disease-Specific Survival (%) 0.25 0.50 0.75
1.00
Figure 3 Kaplan-Meier Cancer-Specific Survival Curve of Patients With Stage IV Sarcomatoid Renal Cell Carcinoma at Diagnosis, Stratified by Performance of Nephrectomy
0.00
Nephrectomy Performed Nephrectomy Not Performed
0 Number at risk cds = 0 192 No nephrectomy cds = 1 238 Nephrectomy
20
40 Months
60
80
4 31
1 5
0 3
0 0
diagnosis and older age were associated with worse DSS, whereas performance of nephrectomy was associated with improved prognosis, even for patients with stage IV disease. Advanced stage at disease presentation has been reported previously for sRCC.1 In our study, we found that the median tumor size at diagnosis was 8.3 cm, and 6 of 10 patients presented with stage IV disease. This is consistent with prior smaller studies that reported median or mean tumor sizes between 9 and 11 cm.3,9,17,18 Regarding stage at diagnosis, prior studies accruing between 100 Table 4 Multivariable Cox Proportional Hazards Model for Disease-Specific Mortality in Patients With Sarcomatoid Renal Cell Carcinoma Variable
HR [ (95% CI)
P
Age
1.01 (1.00-1.02)
.01
Ethnicity White
Reference
Black
1.08 (0.80-1.49)
.61
Other (American Indian, Alaska Native, Asian, Pacific Islander)
0.91 (0.64-1.31)
.62
Stage I
Reference
II
1.76 (0.72-4.34)
.21
III
3.81 (2.18-6.67)
<.001
9.89 (5.80-16.98)
<.001
Performance of nephrectomy
0.53 (0.43-0.66)
<.001
Possessing medical insurance
0.62 (0.36-1.06)
.08
IV
Abbreviations: CI ¼ confidence interval; HR ¼ hazard ratio.
and 200 patients each provide rates of synchronous disseminated disease between 25% and 72%,3,9,17,18 and our study confirms that the majority of patients with sRCC present with synchronous metastases. Of note, among patients with metastatic RCC, sRCC accounts for approximately 20% of cases.19,20 In addition, the average age of 63 years and the male predominance observed in our cohort are in agreement with prior reports in the literature.5,17,21 The advanced disease stage at presentation and the lack of effective systemic treatments explain the poor prognosis of sRCC noted in our study. We found that advanced stage and older age were independently associated with worse DSS, a finding that is in accordance with the current literature.2,5 Additionally, median DSS was 9 months for the whole cohort, and only 5 months for stage IV disease. This is consistent with prior published reports in smaller cohorts, which reported median survival estimates between 6 and 22 months.7,21-27 A notable outlier is the study by Achkar et al,28 where a cohort of 21 patients with metastatic sRCC were treated with high-dose interleukin-2 after nephrectomy; median OS in that group was 30 months overall, and 20 months in the subgroup of patients without objective response. Additionally, the 5-year DSS probability noted in our analysis of patients diagnosed between 2010 and 2015 was 23.5%, indicating no improvement compared with the historic estimates of 33% and 27% reported in previous SEER cohorts in smaller number of patients from 2000 to 2009.9,29 The observed lack of noticeable survival improvement for patients with sRCC in the era of targeted therapies was previously underscored by Keskin et al.8 Indeed, effective systemic treatments for sRCC are still an unmet need.2 Despite the suboptimal efficacy of systemic treatments, nephrectomy can be an effective treatment for improving outcomes,
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Sarcomatoid Renal Cell Carcinoma and in our analysis, we found that performance of nephrectomy was independently associated with improved DSS regardless of disease stage. Nephrectomy is indeed performed with curative intent in localized sRCC, yet risk of recurrence is high and aggressive surveillance of patients is warranted.30 Importantly, a survival benefit from nephrectomy was observed even in patients with stage IV disease, with patients treated surgically having half the risk of disease-specific mortality compared to patients managed nonsurgically, although the margin of benefit was small (median DSS, 7 vs. 4 months). Although cytoreductive nephrectomy combined with systemic therapy has been associated with improved survival in patients with metastatic RCC, the majority of these studies included patients with conventional clear-cell RCC.31 Notably, the CARMENA trial recently showed noninferiority of up-front sunitinib versus nephrectomy followed by sunitinib in OS in patients with clear-cell RCC.32 However, a follow-up meta-analysis reaffirmed the survival benefit of cytoreductive nephrectomy in the era of targeted therapies in both clear-cell and noneclear-cell tumors, highlighting the importance of appropriately selecting patients for such a procedure.33,34 In sRCC specifically, Shuch et al,35 citing the overall poor outcomes of sRCC despite aggressive surgery and postoperative therapy, had suggested up-front systemic therapy in patients with stage IV disease, with cytoreductive nephrectomy reserved for those patients with disease that responded to therapy. Gu et al21 had also reported that among 184 patients with metastatic RCC treated with cytoreductive nephrectomy, sarcomatoid dedifferentiation was associated with poorer progression-free survival and OS. However, Heng et al27 observed a 5-month benefit in OS in 189 patients with metastatic sRCC who had undergone cytoreductive nephrectomy. Our analysis reaffirms these results at a larger scale and supports the recommendation to perform cytoreductive nephrectomy in carefully selected patients with metastatic sRCC with an acceptable performance status and operative risk. Notably, sRCC have been shown to express programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) at a higher percentage than RCC without sarcomatoid dedifferentiation.36 This may imply a potential benefit of up-front immunotherapy for patients with metastatic sRCC, which is currently being actively investigated in prospective studies.2 Concerning potential study limitations, we could not control for selection bias in patients undergoing nephrectomy, as these patients could arguably have less burden of disease or a better performance status—factors that could in turn be affecting the survival benefit observed in this group. Indeed, we found that nephrectomy was more likely to be performed in younger patients; however, nephrectomy was associated with improved DSS in the ensuing multivariable analysis independent of age. Similarly, because of unavailable data, we could not include validated prognostic scores such as the International Metastatic Renal Cell Carcinoma Database Consortium criteria in our regression models.37 Furthermore, the percentage of the sarcomatoid component or the subtype of the epithelioid component (clear cell vs. noneclear cell) were not available in the database, and these data points are known to be modestly associated with survival.8,10,26 Additionally, systemic therapy data are not recorded in SEER, so we could not assess their effect in our observed outcomes, such as whether patients with stage IV disease that benefited from nephrectomy had received up-front
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systemic treatment. However, all our patients were accrued between 2010 and 2015, thus allowing for some homogeneity in the administered systemic regimens.8 Moreover, because analysis of biopsy material may miss the sarcomatoid component of sRCC,8 patients with sRCC who did not undergo nephrectomy may have been missed from our analysis because they may have not been classified correctly as sRCC in the SEER database. In conclusion, most patients with sRCC present with metastatic disease, and the prognosis for this disease remains extremely poor. The survival benefit noted with nephrectomy in our study, coupled with the known suboptimal efficacy of systemic therapies, should prompt consideration of cytoreductive nephrectomy in carefully selected stage IV patients with acceptable surgical risk. Further studies are warranted to assess the efficacy of newer therapeutics (such as PD-1/PD-L1 inhibitors) in this aggressive disease.
Clinical Practice Points sRCC constitutes a rare and aggressive subtype of RCC. Among a recent multi-institutional cohort of 879 patients with
sRCC, the median tumor size was 8.3 cm, and 60.9% of patients presented with metastatic disease. The 5-year DSS probabilities were 77.7%, 67.8%, 35.4%, and 3.5% for patients with stage I, II, III, and IV disease at diagnosis, respectively. Older age and higher tumor stage were associated with worse DSS, whereas performance of nephrectomy was associated with increased DSS, independent of disease stage. On the basis of the above, nephrectomy should be considered in all patients with acceptable surgical risk, including cytoreductive nephrectomy in carefully selected patients with metastatic disease.
Acknowledgments P.M. is supported by a Conquer Cancer Foundation Young Investigator Award and by a Kidney Cancer Association Young Investigator Award.
Disclosure The authors have stated that they have no conflict of interest.
References 1. Zhang L, Wu B, Zha Z, Zhao H, Feng Y. The prognostic value and clinicopathological features of sarcomatoid differentiation in patients with renal cell carcinoma: a systematic review and meta-analysis. Cancer Manage Res 2018; 10: 1687-703. 2. Mouallem NE, Smith SC, Paul AK. Sarcomatoid renal cell carcinoma: biology and treatment advances. Urol Oncol 2018; 36:265-71. 3. 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. 4. Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM. The 2016 WHO Classification of Tumours of the Urinary System and Male Genital OrgansePart A: Renal, Penile, and Testicular Tumours. Eur Urol 2016; 70:93-105. 5. Lebacle C, Pooli A, Bessede T, Irani J, Pantuck AJ, Drakaki A. Epidemiology, biology and treatment of sarcomatoid RCC: current state of the art [e-pub ahead of print], World J Urol, https://doi.org/10.1007/s00345-018-2355-y. Accessed: October 1, 2018. 6. He H, Magi-Galluzzi C. Epithelial-to-mesenchymal transition in renal neoplasms. Adv Anat Pathol 2014; 21:174-80. 7. Kyriakopoulos CE, Chittoria N, Choueiri TK, et al. Outcome of patients with metastatic sarcomatoid renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium. Clin Genitourin Cancer 2015; 13:e79-85.
Michail Alevizakos et al 8. Keskin SK, Msaouel P, Hess KR, et al. Outcomes of patients with renal cell carcinoma and sarcomatoid dedifferentiation treated with nephrectomy and systemic therapies: comparison between the cytokine and targeted therapy eras. J Urol 2017; 198:530-7. 9. Shuch B, Bratslavsky G, Shih J, et al. Impact of pathological tumour characteristics in patients with sarcomatoid renal cell carcinoma. BJU Int 2012; 109:1600-6. 10. Kim T, Zargar-Shoshtari K, Dhillon J, et al. Using percentage of sarcomatoid differentiation as a prognostic factor in renal cell carcinoma. Clin Genitourin Cancer 2015; 13:225-30. 11. National Cancer Institute, Surveillance, Epidemiology, and End Results Program. SEER incidence data, 1973-2015. Available at: https://seer.cancer.gov/data/. Accessed: September 1, 2018. 12. International Association of Cancer Registries. International rules for multiple primary cancers. 2004. Available at: http://www.iacr.com.fr/images/doc/MPrules_ july2004.pdf. Accessed: September 1, 2018. 13. Amin MB, Edge SB, Greene FL, et al, eds. AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer; 2017. 14. Nasioudis D, Alevizakos M, Chapman-Davis E, Witkin SS, Holcomb K. Rhabdomyosarcoma of the lower female genital tract: an analysis of 144 cases. Arch Gynecol Obstet 2017; 296:327-34. 15. Lontos K, Tsagianni A, Msaouel P, Appleman LJ, Nasioudis D. Primary urinary tract lymphoma: rare but aggressive. Anticancer Res 2017; 37:6989-95. 16. Heinze G, Wallisch C, Dunkler D. Variable selection—a review and recommendations for the practicing statistician. Biom J 2018; 60:431-49. 17. 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. 18. 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. 19. Shuch B, Said J, LaRochelle JC, et al. Histologic evaluation of metastases in renal cell carcinoma with sarcomatoid transformation and its implications for systemic therapy. Cancer 2010; 116:616-24. 20. Margulis V, Matin SF, Tannir N, et al. Surgical morbidity associated with administration of targeted molecular therapies before cytoreductive nephrectomy or resection of locally recurrent renal cell carcinoma. J Urol 2008; 180:94-8. 21. Gu L, Li H, Wang H, et al. Presence of sarcomatoid differentiation as a prognostic indicator for survival in surgically treated metastatic renal cell carcinoma. J Cancer Res Clin Oncol 2017; 143:499-508. 22. Golshayan AR, George S, Heng DY, et al. Metastatic sarcomatoid renal cell carcinoma treated with vascular endothelial growth factor-targeted therapy. J Clin Oncol 2009; 27:235-41. 23. Yan Y, Liu L, Zhou J, et al. Clinicopathologic characteristics and prognostic factors of sarcomatoid renal cell carcinoma. J Cancer Res Clin Oncol 2015; 141:345-52.
24. 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. 25. Molina AM, Tickoo SK, Ishill N, et al. Sarcomatoid-variant renal cell carcinoma: treatment outcome and survival in advanced disease. Am J Clin Oncol 2011; 34: 454-9. 26. Nguyen DP, Vilaseca A, Vertosick EA, et al. Histologic subtype impacts cancerspecific survival in patients with sarcomatoid-variant renal cell carcinoma treated surgically. World J Urol 2016; 34:539-44. 27. Heng DY, Wells JC, Rini BI, et al. Cytoreductive nephrectomy in patients with synchronous metastases from renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium. Eur Urol 2014; 66:704-10. 28. Achkar T, Arjunan A, Wang H, et al. High-dose interleukin 2 in patients with metastatic renal cell carcinoma with sarcomatoid features. PLoS One 2017; 12: e0190084. 29. Trudeau V, Larcher A, Sun M, et al. Comparison of oncologic outcomes between sarcomatoid and clear cell renal cell carcinoma. World J Urol 2016; 34:1429-36. 30. Merrill MM, Wood CG, Tannir NM, et al. Clinically nonmetastatic renal cell carcinoma with sarcomatoid dedifferentiation: natural history and outcomes after surgical resection with curative intent. Urol Oncol 2015; 33:166.e21-9. 31. Petrelli F, Coinu A, Vavassori I, et al. Cytoreductive nephrectomy in metastatic renal cell carcinoma treated with targeted therapies: a systematic review with a meta-analysis. Clin Genitourin Cancer 2016; 14:465-72. 32. Mejean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med 2018; 379:417-27. 33. Massari F, Di Nunno V, Gatto L, et al. Should CARMENA really change our attitude towards cytoreductive nephrectomy in metastatic renal cell carcinoma? A systematic review and meta-analysis evaluating cytoreductive nephrectomy in the era of targeted therapy. Target Oncol 2018; 13:705-14. 34. Motzer RJ, Russo P. Cytoreductive nephrectomy—patient selection is key. N Engl J Med 2018; 379:481-2. 35. Shuch B, Said J, La Rochelle JC, et al. Cytoreductive nephrectomy for kidney cancer with sarcomatoid histology—is up-front resection indicated and, if not, is it avoidable? J Urol 2009; 182:2164-71. 36. Joseph RW, Millis SZ, Carballido EM, et al. PD-1 and PD-L1 expression in renal cell carcinoma with sarcomatoid differentiation. Cancer Immunol Res 2015; 3: 1303-7. 37. Heng DY, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factoretargeted agents: results from a large, multicenter study. J Clin Oncol 2009; 27:5794-9.
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Sarcomatoid Renal Cell Carcinoma: Population-Based Study of 879 Patients Michail Alevizakos,1 Apostolos Gaitanidis,2 Dimitrios Nasioudis,3 Pavlos Msaouel,4 Leonard J. Appleman5 Abstract Sarcomatoid renal cell carcinoma constitutes a rare and aggressive subtype of renal cell carcinoma. Among a recent multi-institutional cohort of 879 patients, the majority present with metastatic disease, and overall prognosis is poor; older age and higher disease stage were associated with poorer disease-specific survival (DSS). Notably, performance of nephrectomy was associated with improved DSS independent of disease stage. Background: Sarcomatoid renal cell carcinoma (sRCC) constitutes a rare and aggressive subtype of renal cell carcinoma. We aimed to investigate its clinicopathologic characteristics and outcomes at a national level. Patients and Methods: We accessed the National Cancer Institute’s Surveillance, Epidemiology, and End Results database (2010-2015) and extracted data on patients with sRCC. We estimated median, 1-, 3-, and 5-year disease-specific survival (DSS) probabilities after generation of Kaplan-Meier curves and used multivariable regression to evaluate variables associated with nephrectomy and DSS. Results: A total of 879 patients with sRCC were identified; 60.9% patients had stage IV disease at diagnosis, and the median tumor size was 8.3 cm (interquartile range, 5.5-12 cm). The 5-year DSS were 77.7%, 67.8%, 35.4%, and 3.5% for patients with stage I, II, III, and IV disease at diagnosis, respectively; median DSS was 9 months (interquartile range, 4-42 months) for the entire cohort. Older age (hazard ratio [HR] ¼ 1.01; 95% confidence interval [CI], 1.00-1.02), higher tumor stage (stage III vs. I: HR ¼ 3.81; 95% CI, 2.18-6.67; stage IV vs. I: HR ¼ 9.89; 95% CI, 5.80-16.98), and performance of nephrectomy (HR ¼ 0.53; 95% CI, 0.43-0.66) were found to independently affect DSS. Conclusion: In the largest sRCC cohort to date, we found that most patients present with metastatic disease, and the prognosis for this disease remains extremely poor. Nephrectomy should be considered in all patients with acceptable surgical risk, including cytoreductive nephrectomy in carefully selected patients with metastatic disease. Clinical Genitourinary Cancer, Vol. 17, No. 3, e447-53 ª 2019 Elsevier Inc. All rights reserved. Keywords: Nephrectomy, Prognosis, SEER, SRCC, Survival
Introduction Renal cell carcinoma (RCC) with sarcomatoid dedifferentiation (sarcomatoid renal cell carcinoma, sRCC) constitutes a rare subgroup of RCC, accounting for approximately 5% to 7% of all RCC cases.1-3 It is not a distinct pathologic entity according to the 2016 1
Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA Second Department of Surgery, University General Hospital of Alexandroupoli, Democritus University of Thrace Medical School, Alexandroupoli, Greece 3 Department of Obstetrics and Gynecology, Hospital of the University of Pennsylvania, Philadelphia, PA 4 Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 5 Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, PA 2
Submitted: Nov 4, 2018; Revised: Dec 29, 2018; Accepted: Jan 8, 2019; Epub: Jan 17, 2019 Address for correspondence: Michail Alevizakos, MD, Department of Medicine, UPMC Montefiore Hospital, N-715, 200 Lothrop St, Pittsburgh, PA 15213 Fax: (412) 692-4944; e-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.clgc.2019.01.005
World Health Organization classification because the presence of sarcomatoid components constitutes a dedifferentiation that can occur in all types of RCC.4 Histologically, sRCC thus contains both epithelial (carcinomatous) and mesenchymal (sarcomatoid) components, unlike a true sarcoma of the kidney.5,6 However, it is frequently studied as a distinct clinical entity because it is associated with an aggressive phenotype, advanced stage at diagnosis, and worse overall survival (OS) and disease-specific survival (DSS).1,7 Additionally, it responds poorly to cytotoxic chemotherapy, cytokines, and targeted therapies.2,7,8 Notably, a higher percentage of sarcomatoid features is associated with worse survival.9,10 To delineate the clinicopathologic characteristics and outcomes of patients with sRCC at a national level, we queried the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database. This allowed us to more accurately define outcomes of this disease and their association with potential predictors at the national level.
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Sarcomatoid Renal Cell Carcinoma Table 1 Demographic and Clinical Characteristics of Patients With Sarcomatoid Renal Cell Carcinoma Total (N [ 879)
Nephrectomy Performeda (N [ 577)
Nephrectomy Not Performeda (N [ 295)
29 (10-44)
30 (14-46)
15 (5-35)
Male
613 (69.7%)
406 (70.4%)
203 (68.8%)
Female
266 (30.3%)
171 (29.6%)
92 (31.2%)
63.4 12.1
62 11.9
65.9 11.9
White
713 (81.1%)
465 (80.6%)
241 (81.7%)
Black
103 (11.7%)
65 (11.3%)
38 (12.9%)
56 (6.4%)
41 (7.1%)
15 (5.1%)
7 (0.8%)
6 (1%)
1 (0.3%) 167 (56.6%)
Characteristic Follow-up (mo), median (IQR) Gender
Age (y), mean SD Ethnicity
Other (American Indian, Alaska Native, Asian, Pacific Islander) Unknown Marital Status Married
524 (59.6%)
352 (61%)
Divorced, separated, or widowed
171 (19.5%)
100 (17.3%)
71 (24.1%)
Single or never married
139 (15.8%)
92 (16%)
45 (15.3%)
45 (5.1%)
33 (5.7%)
12 (4%)
Unknown Insurance Status Insured
831 (94.5%)
545 (94.4%)
279 (94.6%)
Not insured
27 (3.1%)
16 (2.8%)
11 (3.7%)
Unknown
21 (2.4%)
16 (2.8%)
5 (1.7%)
I
97 (11%)
91 (15.7%)
6 (2%)
II
30 (3.4%)
27 (4.7%)
III
196 (22.3%)
188 (32.6%)
8 (2.7%)
IV
535 (60.9%)
264 (45.8%)
267 (90.5%)
21 (2.4%)
7 (1.2%)
11 (3.8%)
Lung
305 (34.6%)
133 (23.1%)
170 (57.6%)
Bone
207 (23.5%)
78 (13.5%)
129 (43.7%)
Liver
111 (12.6%)
39 (6.8%)
72 (24.4%)
45 (5.1%)
14 (2.4%)
31 (10.5%)
Stage
Unknown
3 (1%)
Metastatic Disease
Brain Nephrectomy Performed Yes Radical nephrectomy
577 (65.6%) 425
Simple nephrectomy/nephroureterectomy
43
Partial nephrectomy
61
Nephrectomy NOS No Unknown
48 295 (33.6%) 7 (0.8%)
Abbreviations: IQR ¼ interquartile range; NOS ¼ not otherwise specified. a Performance of nephrectomy was not specified in 7 patients.
Patients and Methods A cohort of patients with sRCC was drawn from the SEER database, which incorporates high-quality data deriving from 18 cancer registries and covers approximately 34.6% of the total US population based on the 2010 census.11 All patient data are deidentified and available to the public for research purposes. As such, the SEER database permits the study of malignancies with an extremely low incidence. Because SEER contains only deidentified
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data, no institutional review board approval was required for the conduct of this study. The following criteria were applied to identify eligible cases of sRCC: microscopically confirmed tumor, ICD-O-3 histology codes 8318/3 (“Renal cell carcinoma, sarcomatoid”), tumor diagnosed between January 1, 2010, and December 31, 2015, active followup, and reported tumor being the primary lesion by the rules of the International Association of Cancer Registry.12 We selected the
Michail Alevizakos et al Table 2 Disease-Specific Survival Probabilities of Patients With Sarcomatoid Renal Cell Carcinoma by Disease Stage Stage Survival 1 year 3 year 5 year Survival (mo), median (IQR)
I
II
III
88% (78.1-93.6) 77.7% (66.6-86.1) 77.7% (65.6-86.1) Not reached
82.7% (60.1-93.2) 67.8% (43.7-83.3) 67.8% (43.7-83.3) Not reached
67% (58.5%-74.2%) 37.1% (28.1-46.2) 35.4% (26.2-44.6) 18 (8-not reached)
IV 23.8% 7% 3.5% 5
All Stages Combined
(19.5-28.3) (4.3-10.6) (1.4-7.3) (2-12)
43.7% 25.8% 23.5% 9
(39.7-49.5) (22.1-29.7) (19.7-27.6) (4-42)
Data in parentheses are 95% confidence interval unless otherwise indicated. Abbreviations: IQR ¼ interquartile range; NA ¼ not applicable.
aforementioned period of observation because it was the one containing data on site-specific synchronous metastases. We used the “case listing” option to extract demographic, clinicopathologic, and survival data. Specifically, we extracted information on patient gender, age at diagnosis, ethnicity, marital status, and insurance status. Additionally, we recorded tumor size and stage at diagnosis, the presence of synchronous bone, brain, lung, and liver metastases, and whether patients had undergone nephrectomy. Staging information was based on the derived 8th edition of the American Joint Committee on Cancer staging system.13 We also gathered data on recorded survival and cause of death for all patients. We generated Kaplan-Meier curves to determine median and 1-, 3-, and 5-year DSS probabilities.14 We used the reverse KaplanMeier method to calculate the median follow-up time. For DSS, only death attributable to sRCC was considered to be an event, and patients diagnosed with more than one primary tumor were excluded to prevent confounding.15 We used similar methodology to calculate OS, in which case death from any cause was considered an event. To avoid the inherent inferential limitations associated
with these approaches, we did not perform variable selection by univariate comparisons or stepwise procedures.16 We instead generated prespecified regression models with all covariates chosen on the basis of background knowledge and theoretical considerations.16 Accordingly, we performed multivariable Cox regression to identify the effect of age, ethnicity, insurance status, tumor stage, and performance of nephrectomy in DSS. We also performed a multivariable logistic regression to identify the effect of age, gender, ethnicity, marital status, insurance status, tumor stage, and presence of metastatic (M1) disease on whether nephrectomy was performed. Because sRCC is by definition grade 4,13 grade was not included in our analysis. Statistical analysis was performed by Stata 13 software package (StataCorp, College Station, TX), and the a level of statistical significance was set at 0.05.
Results Overall, we identified 879 patients with sRCC; median follow-up time was 29 months (interquartile range [IQR], 10-44 months). At diagnosis, 97 patients (11%) had stage I disease, 30 (3.4%) stage II
Disease-Specific Survival (%) 0.00 0.25 0.50 0.75 1.00
Figure 1 Kaplan-Meier Cancer-Specific Survival Curve of Patients With Sarcomatoid Renal Cell Carcinoma, Stratified by Stage at Diagnosis
Number at risk Stage = 1 Stage = 2 Stage = 3 Stage = 4
0
20
40 Months
60
80
79 27 157 431
52 14 53 35
24 4 24 6
10 0 7 3
0 0 0 0
Stage = 1 Stage = 3
Stage = 2 Stage = 4
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Sarcomatoid Renal Cell Carcinoma
0.00
Overall Survival (%) 0.25 0.50 0.75 1.00
Figure 2 Kaplan-Meier Overall Survival Curve of Patients With Sarcomatoid Renal Cell Carcinoma, Stratified by Stage at Diagnosis
Number at risk Stage = 1 Stage = 2 Stage = 3 Stage = 4
0
20
40 Months
60
80
79 27 157 431
52 14 53 35
24 4 24 6
10 0 7 3
0 0 0 0
Stage = 1 Stage = 3
disease, 196 (22.3%) stage III disease, and 535 (60.9%) stage IV disease; disease stage was unknown for 21 patients (2.4%). The median tumor size was 83 mm (IQR, 55-120 mm). The clinical and demographic characteristics of the studied cohort are listed in Table 1. In multivariable analysis, older age (odds ratio [OR] ¼ 0.96; 95% confidence interval [CI], 0.94-0.97), presence of M1 disease (OR ¼ 0.26; 95% CI, 0.12-0.53), and stage IV disease (OR ¼ 0.16; 95% CI, 0.05-0.52) were inversely and independently associated with performance of nephrectomy. Of the 879 available patients, data from 759 (86.3%) were utilized to calculate DSS and OS, as 120 patients (13.7%) had been diagnosed with more than one primary tumor. The 1-, 3-, and 5-year DSS probabilities for all patients were 43.7%, 25.8%, and 23.5%, respectively, and the median DSS for the entire cohort was 9 months (IQR, 4-42 months). Additionally, the 1-, 3-, and 5-year
Table 3 Disease-Specific Survival Probabilities of Patients With Stage IV Sarcomatoid Renal Cell Carcinoma According to Performance of Nephrectomy
Survival 1 year 3 year 5 year Survival (mo), median (IQR)
Stage IV Disease With Nephrectomy 33.7% 10.8% 6.2% 7
(26.7-39.5) (6.5-16.5) (2.5-12.3) (3-17)
Stage IV Disease Without Nephrectomy 11.5% 1.9% 0% 4
Data in parentheses are 95% confidence interval unless otherwise indicated. Abbreviations: IQR ¼ interquartile range; NA ¼ not applicable.
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(7-17.2) (0.4-5.9) (NA) (2-7)
Stage = 2 Stage = 4
OS probabilities for all patients were 41.9%, 22.9%, and 20.2%, respectively, and the median OS for the entire cohort was 8 months (IQR, 3-30 month). DSS probabilities by stage are provided in Table 2 and Figure 1, and OS probabilities by stage are depicted in Figure 2. Among 472 patients with stage IV disease, the 1-, 3-, and 5-year DSS probabilities for patients who underwent nephrectomy were 33.7%, 10.8%, and 6.2%, respectively, whereas the same DSS probabilities were 11.5%, 1.9%, and 0 for patients who did not undergo nephrectomy. Among these patients, median DSS was 7 months (IQR, 3-17 months) among patients who underwent nephrectomy versus 4 months (IQR, 2-7 months) for patients treated nonsurgically. DSS probabilities stratified by performance of nephrectomy for patients with stage IV disease are provided in Table 3 and Figure 3. In multivariable analysis, older age (hazard ratio [HR] ¼ 1.01; 95% CI, 1.00-1.02), higher tumor stage (stage III vs. I: HR ¼ 3.81; 95% CI, 2.18-6.67; stage IV vs. I: HR ¼ 9.89; 95% CI, 5.80-16.98), and performance of nephrectomy (HR ¼ 0.53; 95% CI, 0.43-0.66) were found to be significantly and independently associated with DSS (Table 4).
Discussion RCC with sarcomatoid dedifferentiation constitutes an aggressive subtype of RCC that portends a poor prognosis.1 In our study, which to our knowledge contains the largest contemporary studied cohort of sRCC patients, we explored the epidemiology of this tumor by utilizing recent aggregate data from a multi-institutional national registry. Importantly, we found that the majority of patients with sRCC present with large primary tumors as well as synchronous metastases, and patients overall have a poor median DSS of 9 months. We also identified that a higher tumor stage at
Michail Alevizakos et al
Disease-Specific Survival (%) 0.25 0.50 0.75
1.00
Figure 3 Kaplan-Meier Cancer-Specific Survival Curve of Patients With Stage IV Sarcomatoid Renal Cell Carcinoma at Diagnosis, Stratified by Performance of Nephrectomy
0.00
Nephrectomy Performed Nephrectomy Not Performed
0 Number at risk cds = 0 192 No nephrectomy cds = 1 238 Nephrectomy
20
40 Months
60
80
4 31
1 5
0 3
0 0
diagnosis and older age were associated with worse DSS, whereas performance of nephrectomy was associated with improved prognosis, even for patients with stage IV disease. Advanced stage at disease presentation has been reported previously for sRCC.1 In our study, we found that the median tumor size at diagnosis was 8.3 cm, and 6 of 10 patients presented with stage IV disease. This is consistent with prior smaller studies that reported median or mean tumor sizes between 9 and 11 cm.3,9,17,18 Regarding stage at diagnosis, prior studies accruing between 100 Table 4 Multivariable Cox Proportional Hazards Model for Disease-Specific Mortality in Patients With Sarcomatoid Renal Cell Carcinoma Variable
HR [ (95% CI)
P
Age
1.01 (1.00-1.02)
.01
Ethnicity White
Reference
Black
1.08 (0.80-1.49)
.61
Other (American Indian, Alaska Native, Asian, Pacific Islander)
0.91 (0.64-1.31)
.62
Stage I
Reference
II
1.76 (0.72-4.34)
.21
III
3.81 (2.18-6.67)
<.001
9.89 (5.80-16.98)
<.001
Performance of nephrectomy
0.53 (0.43-0.66)
<.001
Possessing medical insurance
0.62 (0.36-1.06)
.08
IV
Abbreviations: CI ¼ confidence interval; HR ¼ hazard ratio.
and 200 patients each provide rates of synchronous disseminated disease between 25% and 72%,3,9,17,18 and our study confirms that the majority of patients with sRCC present with synchronous metastases. Of note, among patients with metastatic RCC, sRCC accounts for approximately 20% of cases.19,20 In addition, the average age of 63 years and the male predominance observed in our cohort are in agreement with prior reports in the literature.5,17,21 The advanced disease stage at presentation and the lack of effective systemic treatments explain the poor prognosis of sRCC noted in our study. We found that advanced stage and older age were independently associated with worse DSS, a finding that is in accordance with the current literature.2,5 Additionally, median DSS was 9 months for the whole cohort, and only 5 months for stage IV disease. This is consistent with prior published reports in smaller cohorts, which reported median survival estimates between 6 and 22 months.7,21-27 A notable outlier is the study by Achkar et al,28 where a cohort of 21 patients with metastatic sRCC were treated with high-dose interleukin-2 after nephrectomy; median OS in that group was 30 months overall, and 20 months in the subgroup of patients without objective response. Additionally, the 5-year DSS probability noted in our analysis of patients diagnosed between 2010 and 2015 was 23.5%, indicating no improvement compared with the historic estimates of 33% and 27% reported in previous SEER cohorts in smaller number of patients from 2000 to 2009.9,29 The observed lack of noticeable survival improvement for patients with sRCC in the era of targeted therapies was previously underscored by Keskin et al.8 Indeed, effective systemic treatments for sRCC are still an unmet need.2 Despite the suboptimal efficacy of systemic treatments, nephrectomy can be an effective treatment for improving outcomes,
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Sarcomatoid Renal Cell Carcinoma and in our analysis, we found that performance of nephrectomy was independently associated with improved DSS regardless of disease stage. Nephrectomy is indeed performed with curative intent in localized sRCC, yet risk of recurrence is high and aggressive surveillance of patients is warranted.30 Importantly, a survival benefit from nephrectomy was observed even in patients with stage IV disease, with patients treated surgically having half the risk of disease-specific mortality compared to patients managed nonsurgically, although the margin of benefit was small (median DSS, 7 vs. 4 months). Although cytoreductive nephrectomy combined with systemic therapy has been associated with improved survival in patients with metastatic RCC, the majority of these studies included patients with conventional clear-cell RCC.31 Notably, the CARMENA trial recently showed noninferiority of up-front sunitinib versus nephrectomy followed by sunitinib in OS in patients with clear-cell RCC.32 However, a follow-up meta-analysis reaffirmed the survival benefit of cytoreductive nephrectomy in the era of targeted therapies in both clear-cell and noneclear-cell tumors, highlighting the importance of appropriately selecting patients for such a procedure.33,34 In sRCC specifically, Shuch et al,35 citing the overall poor outcomes of sRCC despite aggressive surgery and postoperative therapy, had suggested up-front systemic therapy in patients with stage IV disease, with cytoreductive nephrectomy reserved for those patients with disease that responded to therapy. Gu et al21 had also reported that among 184 patients with metastatic RCC treated with cytoreductive nephrectomy, sarcomatoid dedifferentiation was associated with poorer progression-free survival and OS. However, Heng et al27 observed a 5-month benefit in OS in 189 patients with metastatic sRCC who had undergone cytoreductive nephrectomy. Our analysis reaffirms these results at a larger scale and supports the recommendation to perform cytoreductive nephrectomy in carefully selected patients with metastatic sRCC with an acceptable performance status and operative risk. Notably, sRCC have been shown to express programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) at a higher percentage than RCC without sarcomatoid dedifferentiation.36 This may imply a potential benefit of up-front immunotherapy for patients with metastatic sRCC, which is currently being actively investigated in prospective studies.2 Concerning potential study limitations, we could not control for selection bias in patients undergoing nephrectomy, as these patients could arguably have less burden of disease or a better performance status—factors that could in turn be affecting the survival benefit observed in this group. Indeed, we found that nephrectomy was more likely to be performed in younger patients; however, nephrectomy was associated with improved DSS in the ensuing multivariable analysis independent of age. Similarly, because of unavailable data, we could not include validated prognostic scores such as the International Metastatic Renal Cell Carcinoma Database Consortium criteria in our regression models.37 Furthermore, the percentage of the sarcomatoid component or the subtype of the epithelioid component (clear cell vs. noneclear cell) were not available in the database, and these data points are known to be modestly associated with survival.8,10,26 Additionally, systemic therapy data are not recorded in SEER, so we could not assess their effect in our observed outcomes, such as whether patients with stage IV disease that benefited from nephrectomy had received up-front
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systemic treatment. However, all our patients were accrued between 2010 and 2015, thus allowing for some homogeneity in the administered systemic regimens.8 Moreover, because analysis of biopsy material may miss the sarcomatoid component of sRCC,8 patients with sRCC who did not undergo nephrectomy may have been missed from our analysis because they may have not been classified correctly as sRCC in the SEER database. In conclusion, most patients with sRCC present with metastatic disease, and the prognosis for this disease remains extremely poor. The survival benefit noted with nephrectomy in our study, coupled with the known suboptimal efficacy of systemic therapies, should prompt consideration of cytoreductive nephrectomy in carefully selected stage IV patients with acceptable surgical risk. Further studies are warranted to assess the efficacy of newer therapeutics (such as PD-1/PD-L1 inhibitors) in this aggressive disease.
Clinical Practice Points sRCC constitutes a rare and aggressive subtype of RCC. Among a recent multi-institutional cohort of 879 patients with
sRCC, the median tumor size was 8.3 cm, and 60.9% of patients presented with metastatic disease. The 5-year DSS probabilities were 77.7%, 67.8%, 35.4%, and 3.5% for patients with stage I, II, III, and IV disease at diagnosis, respectively. Older age and higher tumor stage were associated with worse DSS, whereas performance of nephrectomy was associated with increased DSS, independent of disease stage. On the basis of the above, nephrectomy should be considered in all patients with acceptable surgical risk, including cytoreductive nephrectomy in carefully selected patients with metastatic disease.
Acknowledgments P.M. is supported by a Conquer Cancer Foundation Young Investigator Award and by a Kidney Cancer Association Young Investigator Award.
Disclosure The authors have stated that they have no conflict of interest.
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