BACKGROUND: Renal cell carcinoma with sarcomatoid dedifferentiation represents a rare histological entity characterized by aggressive behavior, limited efficacy of tyrosine kinase inhibitors or mTOR inhibitors, and poor outcome. The immune checkpoint inhibitor therapy regimen combining ipilimumab with nivolumab represents a new standard of care for this patient population due to a hitherto unprecedented response rate and overall survival. On the other hand, the role of cytoreductive nephrectomy in metastatic renal cell carcinoma, in particular, with sarcomatoid histology, remains controversial. PATIENT AND METHODS: In the present case series, we report six patients with locally advanced or synchronous metastatic sarcomatoid renal cell carcinoma and intermediate or poor International Metastatic RCC Database Consortium (IMDC) risk score, five of whom were successfully subjected to cytoreductive nephrectomy. RESULTS: All six patients received the combination regimen of ipilimumab with nivolumab. Five of these patients underwent upfront cytoreductive nephrectomy followed by systemic treatment without any significant delay, with a durable treatment outcome. Notably, two patients with poor prognostic features achieved a long-term major partial response to therapy. We also performed a review of the literature on optimal treatment strategies for patients with sarcomatoid renal cell carcinoma. CONCLUSION: Herein, we highlight the feasibility of performing cytoreductive nephrectomy in patients with intermediate/poor prognosis metastatic renal cell carcinoma with sarcomatoid dedifferentiation followed by immunotherapy with ipilimumab and nivolumab. To enhance the chances of immunotherapy success, cytoreductive nephrectomy should also be considered for patients presenting with a disease with adverse prognostic parameters.

Department of Clinical and Molecular Pathology Faculty of Medicine and Dentistry University Hospital Olomouc Palacky University 771 47 Olomouc Czech Republic

Department of Oncology Faculty of Medicine and Dentistry University Hospital Olomouc Palacky University 771 47 Olomouc Czech Republic

Department of Urology Faculty of Medicine and Dentistry University Hospital Olomouc Palacky University 771 47 Olomouc Czech Republic

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry University Hospital Olomouc Palacky University 771 47 Olomouc Czech Republic

Zobrazit více v PubMed

Sung H., Ferlay J., Siegel R.L., Laversanne M., Soerjomataram I., Jemal A., Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021;71:209–249. doi: 10.3322/caac.21660. PubMed DOI

Kim T., Zargar-Shoshtari K., Dhillon J., Lin H.Y., Yue B., Fishman M., Sverrisson E.F., Spiess P.E., Gupta S., Poch M.A., et al. Using percentage of sarcomatoid differentiation as a prognostic factor in renal cell carcinoma. Clin. Genitourin. Cancer. 2015;13:225–230. doi: 10.1016/j.clgc.2014.12.001. PubMed DOI

de Velasco G., McKay R.R., Lin X., Moreira R.B., Simantov R., Choueiri T.K. Comprehensive Analysis of Survival Outcomes in Non-Clear Cell Renal Cell Carcinoma Patients Treated in Clinical Trials. Clin. Genitourin. Cancer. 2017;15:652–660.e651. doi: 10.1016/j.clgc.2017.03.004. PubMed DOI

Zhang B.Y., Thompson R.H., Lohse C.M., Leibovich B.C., Boorjian S.A., Cheville J.C., Costello B.A. A novel prognostic model for patients with sarcomatoid renal cell carcinoma. BJU Int. 2015;115:405–411. doi: 10.1111/bju.12781. PubMed DOI

Kyriakopoulos C.E., Chittoria N., Choueiri T.K., Kroeger N., Lee J.L., Srinivas S., Knox J.J., Bjarnason G.A., Ernst S.D., Wood L.A., 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–e85. doi: 10.1016/j.clgc.2014.08.011. PubMed DOI

Adibi M., Thomas A.Z., Borregales L.D., Merrill M.M., Slack R.S., Chen H.C., Sircar K., Murugan P., Tamboli P., Jonasch E., et al. Percentage of sarcomatoid component as a prognostic indicator for survival in renal cell carcinoma with sarcomatoid dedifferentiation. Urol. Oncol. 2015;33:427.e17–427.e23. doi: 10.1016/j.urolonc.2015.04.011. PubMed DOI PMC

Moch H., Cubilla A.L., Humphrey P.A., Reuter V.E., Ulbright T.M. The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours. Eur. Urol. 2016;70:93–105. doi: 10.1016/j.eururo.2016.02.029. PubMed DOI

Debien V., Thouvenin J., Lindner V., Barthélémy P., Lang H., Flippot R., Malouf G.G. Sarcomatoid Dedifferentiation in Renal Cell Carcinoma: From Novel Molecular Insights to New Clinical Opportunities. Cancers. 2019;12:99. doi: 10.3390/cancers12010099. PubMed DOI PMC

Voss M.H., Bastos D.A., Karlo C.A., Ajeti A., Hakimi A.A., Feldman D.R., Hsieh J.J., Molina A.M., Patil S., Motzer R.J. Treatment outcome with mTOR inhibitors for metastatic renal cell carcinoma with nonclear and sarcomatoid histologies. Ann. Oncol. 2014;25:663–668. doi: 10.1093/annonc/mdt578. PubMed DOI PMC

Alevizakos M., Gaitanidis A., Nasioudis D., Msaouel P., Appleman L.J. Sarcomatoid Renal Cell Carcinoma: Population-Based Study of 879 Patients. Clin. Genitourin. Cancer. 2019;17:e447–e453. doi: 10.1016/j.clgc.2019.01.005. PubMed DOI

Shuch B., Said J., La Rochelle J.C., Zhou Y., Li G., Klatte T., Kabbinaavar F.F., Pantuck A.J., Belldegrun A.S. Cytoreductive nephrectomy for kidney cancer with sarcomatoid histology--is up-front resection indicated and, if not, is it avoidable? J. Urol. 2009;182:2164–2171. doi: 10.1016/j.juro.2009.07.049. PubMed DOI PMC

von Minckwitz G., Untch M., Blohmer J.U., Costa S.D., Eidtmann H., Fasching P.A., Gerber B., Eiermann W., Hilfrich J., Huober J., et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J. Clin. Oncol. 2012;30:1796–1804. doi: 10.1200/JCO.2011.38.8595. PubMed DOI

Tannir N.M., Signoretti S., Choueiri T.K., McDermott D.F., Motzer R.J., Flaifel A., Pignon J.C., Ficial M., Frontera O.A., George S., et al. Efficacy and Safety of Nivolumab Plus Ipilimumab versus Sunitinib in First-line Treatment of Patients with Advanced Sarcomatoid Renal Cell Carcinoma. Clin. Cancer Res. 2021;27:78–86. doi: 10.1158/1078-0432.CCR-20-2063. PubMed DOI PMC

Rini B.I., Plimack E.R., Stus V., Gafanov R., Hawkins R., Nosov D., Pouliot F., Soulieres D., Melichar B., Vynnychenko I., et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for metastatic renal cell carcinoma (mRCC): Outcomes in the combined IMDC intermediate/poor risk and sarcomatoid subgroups of the phase 3 KEYNOTE-426 study. J. Clin. Oncol. 2019;37:4500. doi: 10.1200/JCO.2019.37.15_suppl.4500. DOI

Rini B.I., Motzer R.J., Powles T., McDermott D.F., Escudier B., Donskov F., Hawkins R.E., Bracarda S., Bedke J., De Giorgi U., et al. Atezolizumab (atezo) plus bevacizumab (bev) versus sunitinib (sun) in pts with untreated metastatic renal cell carcinoma (mRCC) and sarcomatoid (sarc) histology: IMmotion151 subgroup analysis. J. Clin. Oncol. 2019;37:4512. doi: 10.1200/JCO.2019.37.15_suppl.4512. DOI

Choueiri T.K., Larkin J., Pal S., Motzer R.J., Rini B.I., Venugopal B., Alekseev B., Miyake H., Gravis G., Bilen M.A., et al. Efficacy and correlative analyses of avelumab plus axitinib versus sunitinib in sarcomatoid renal cell carcinoma: Post hoc analysis of a randomized clinical trial. ESMO Open. 2021;6:100101. doi: 10.1016/j.esmoop.2021.100101. PubMed DOI PMC

Hwang J.K., Agarwal N., Brugarolas J., Zhang T. Checking the Hippo in Sarcomatoid Renal Cell Carcinoma with Immunotherapy. Clin. Cancer Res. 2021;27:5–7. doi: 10.1158/1078-0432.CCR-20-3506. PubMed DOI PMC

Choueiri T.K., Larkin J.M.G., Pal S.K., Motzer R.J., Venugopal B., Alekseev B.Y., Miyake H., Gravis G., Bilen M.A., Chudnovsky A., et al. Efficacy and biomarker analysis of patients (pts) with advanced renal cell carcinoma (aRCC) with sarcomatoid histology (sRCC): Subgroup analysis from the phase III JAVELIN renal 101 trial of first-line avelumab plus axitinib (A plus Ax) vs sunitinib (S) Ann. Oncol. 2019;30:361. doi: 10.1093/annonc/mdz249.009. PubMed DOI

Iacovelli R., Ciccarese C., Bria E., Bracarda S., Porta C., Procopio G., Tortora G. Patients with sarcomatoid renal cell carcinoma—Re-defining the first-line of treatment: A meta-analysis of randomised clinical trials with immune checkpoint inhibitors. Eur. J. Cancer. 2020;136:195–203. doi: 10.1016/j.ejca.2020.06.008. PubMed DOI

Malouf G.G., Ali S.M., Wang K., Balasubramanian S., Ross J.S., Miller V.A., Stephens P.J., Khayat D., Pal S.K., Su X., et al. Genomic Characterization of Renal Cell Carcinoma with Sarcomatoid Dedifferentiation Pinpoints Recurrent Genomic Alterations. Eur. Urol. 2016;70:348–357. doi: 10.1016/j.eururo.2016.01.051. PubMed DOI

Turajlic S., Xu H., Litchfield K., Rowan A., Horswell S., Chambers T., O’Brien T., Lopez J.I., Watkins T.B.K., Nicol D., et al. Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal. Cell. 2018;173:595–610.e511. doi: 10.1016/j.cell.2018.03.043. PubMed DOI PMC

Kawakami F., Sircar K., Rodriguez-Canales J., Fellman B.M., Urbauer D.L., Tamboli P., Tannir N.M., Jonasch E., Wistuba I.I., Wood C.G., et al. Programmed cell death ligand 1 and tumor-infiltrating lymphocyte status in patients with renal cell carcinoma and sarcomatoid dedifferentiation. Cancer. 2017;123:4823–4831. doi: 10.1002/cncr.30937. PubMed DOI PMC

Joseph R.W., Millis S.Z., Carballido E.M., Bryant D., Gatalica Z., Reddy S., Bryce A.H., Vogelzang N.J., Stanton M.L., Castle E.P., et al. PD-1 and PD-L1 Expression in Renal Cell Carcinoma with Sarcomatoid Differentiation. Cancer Immunol. Res. 2015;3:1303–1307. doi: 10.1158/2326-6066.CIR-15-0150. PubMed DOI PMC

Gupta S., Cheville J.C., Jungbluth A.A., Zhang Y., Zhang L., Chen Y.B., Tickoo S.K., Fine S.W., Gopalan A., Al-Ahmadie H.A., et al. JAK2/PD-L1/PD-L2 (9p24.1) amplifications in renal cell carcinomas with sarcomatoid transformation: Implications for clinical management. Mod. Pathol. 2019;32:1344–1358. doi: 10.1038/s41379-019-0269-x. PubMed DOI PMC

Yoshida T., Ohe C., Ikeda J., Atsumi N., Ohsugi H., Sugi M., Higasa K., Saito R., Tsuta K., Matsuda T., et al. Eosinophilic features in clear cell renal cell carcinoma correlate with outcomes of immune checkpoint and angiogenesis blockade. J. Immunother. Cancer. 2021;9:e002922. doi: 10.1136/jitc-2021-002922. PubMed DOI PMC

Wang T., Lu R., Kapur P., Jaiswal B.S., Hannan R., Zhang Z., Pedrosa I., Luke J.J., Zhang H., Goldstein L.D., et al. An Empirical Approach Leveraging Tumorgrafts to Dissect the Tumor Microenvironment in Renal Cell Carcinoma Identifies Missing Link to Prognostic Inflammatory Factors. Cancer Discov. 2018;8:1142–1155. doi: 10.1158/2159-8290.CD-17-1246. PubMed DOI PMC

Wang Z., Kim T.B., Peng B., Karam J., Creighton C., Joon A., Kawakami F., Trevisan P., Jonasch E., Chow C.W., et al. Sarcomatoid Renal Cell Carcinoma Has a Distinct Molecular Pathogenesis, Driver Mutation Profile, and Transcriptional Landscape. Clin. Cancer Res. 2017;23:6686–6696. doi: 10.1158/1078-0432.CCR-17-1057. PubMed DOI PMC

Singla N., Ghandour R.A., Margulis V. Is cytoreductive nephrectomy relevant in the immunotherapy era? Curr. Opin. Urol. 2019;29:526–530. doi: 10.1097/MOU.0000000000000659. PubMed DOI

Singla N., Hakimi A.A., Margulis V. Editorial: The evolving role of cytoreductive nephrectomy. Curr. Opin. Urol. 2019;29:505–506. doi: 10.1097/MOU.0000000000000653. PubMed DOI

Escudier B., Porta C., Schmidinger M., Rioux-Leclercq N., Bex A., Khoo V., Grünwald V., Gillessen S., Horwich A. Renal Cell Carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2019;30:706–720. doi: 10.1093/annonc/mdz056. PubMed DOI

Conti S.L., Thomas I.C., Hagedorn J.C., Chung B.I., Chertow G.M., Wagner T.H., Brooks J.D., Srinivas S., Leppert J.T. Utilization of cytoreductive nephrectomy and patient survival in the targeted therapy era. Int. J. Cancer. 2014;134:2245–2252. doi: 10.1002/ijc.28553. PubMed DOI PMC

Mathieu R., Pignot G., Ingles A., Crepel M., Bigot P., Bernhard J.C., Joly F., Guy L., Ravaud A., Azzouzi A.R., et al. Nephrectomy improves overall survival in patients with metastatic renal cell carcinoma in cases of favorable MSKCC or ECOG prognostic features. Urol. Oncol. 2015;33:339.e9–339.e15. doi: 10.1016/j.urolonc.2015.05.014. PubMed DOI

Heng D.Y., Wells J.C., Rini B.I., Beuselinck B., Lee J.L., Knox J.J., Bjarnason G.A., Pal S.K., Kollmannsberger C.K., Yuasa T., 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;66:704–710. doi: 10.1016/j.eururo.2014.05.034. PubMed DOI

Choueiri T.K., Xie W., Kollmannsberger C., North S., Knox J.J., Lampard J.G., McDermott D.F., Rini B.I., Heng D.Y.C. The Impact of Cytoreductive Nephrectomy on Survival of Patients with Metastatic Renal Cell Carcinoma Receiving Vascular Endothelial Growth Factor Targeted Therapy. J. Urol. 2011;185:60–66. doi: 10.1016/j.juro.2010.09.012. PubMed DOI

Alhalabi O., Karam J.A., Tannir N.M. Evolving role of cytoreductive nephrectomy in metastatic renal cell carcinoma of variant histology. Curr. Opin. Urol. 2019;29:521–525. doi: 10.1097/MOU.0000000000000661. PubMed DOI

Kassouf W., Sanchez-Ortiz R., Tamboli P., Tannir N., Jonasch E., Merchant M.M., Matin S., Swanson D.A., Wood C.G. Cytoreductive nephrectomy for metastatic renal cell carcinoma with nonclear cell histology. J. Urol. 2007;178:1896–1900. doi: 10.1016/j.juro.2007.07.037. PubMed DOI

Blum K.A., Gupta S., Tickoo S.K., Chan T.A., Russo P., Motzer R.J., Karam J.A., Hakimi A.A. Sarcomatoid renal cell carcinoma: Biology, natural history and management. Nat. Rev. Urol. 2020;17:659–678. doi: 10.1038/s41585-020-00382-9. PubMed DOI PMC

Adashek J.J., Zhang Y., Skelton W.P.t., Bilotta A., Chahoud J., Zemp L., Li J., Dhillon J., Manley B., Spiess P.E. Dissecting Outcomes: Should Cytoreductive Nephrectomy Be Performed for Patients with Metastatic Renal Cell Carcinoma with Sarcomatoid Dedifferentiation? Front. Oncol. 2020;10:627025. doi: 10.3389/fonc.2020.627025. PubMed DOI PMC

Singla N., Hutchinson R.C., Ghandour R.A., Freifeld Y., Fang D., Sagalowsky A.I., Lotan Y., Bagrodia A., Margulis V., Hammers H.J., et al. Improved survival after cytoreductive nephrectomy for metastatic renal cell carcinoma in the contemporary immunotherapy era: An analysis of the National Cancer Database. Urol. Oncol. 2020;38:604.e9–604.e17. doi: 10.1016/j.urolonc.2020.02.029. PubMed DOI PMC

Dilme R.V., Rivas J.G., Campi R., Puente J., Jerez T., Enikeev D., Esperto F., Sierra J.M. Cytoreductive Nephrectomy in the Management of Metastatic Renal Cell Carcinoma: Is There Still a Debate? Curr. Urol. Rep. 2021;22:54. doi: 10.1007/s11934-021-01073-7. PubMed DOI

Mejean A., Ravaud A., Thezenas S., Colas S., Beauval J.B., Bensalah K., Geoffrois L., Thiery-Vuillemin A., Cormier L., Lang H., et al. Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma. N. Engl. J. Med. 2018;379:417–427. doi: 10.1056/NEJMoa1803675. PubMed DOI

Bex A., Albiges L., Ljungberg B., Bensalah K., Dabestani S., Giles R.H., Hofmann F., Hora M., Kuczyk M.A., Lam T.B., et al. Updated European Association of Urology Guidelines for Cytoreductive Nephrectomy in Patients with Synchronous Metastatic Clear-cell Renal Cell Carcinoma. Eur. Urol. 2018;74:805–809. doi: 10.1016/j.eururo.2018.08.008. PubMed DOI

Bex A., Mulders P., Jewett M., Wagstaff J., van Thienen J.V., Blank C.U., van Velthoven R., Del Pilar Laguna M., Wood L., van Melick H.H.E., et al. Comparison of Immediate vs Deferred Cytoreductive Nephrectomy in Patients with Synchronous Metastatic Renal Cell Carcinoma Receiving Sunitinib: The SURTIME Randomized Clinical Trial. JAMA Oncol. 2019;5:164–170. doi: 10.1001/jamaoncol.2018.5543. PubMed DOI PMC

Abu-Ghanem Y., van Thienen J.V., Blank C., Aarts M.J.B., Jewett M., de Jong I.J., Lattouf J.B., van Melick H.H.E., Wood L., Mulders P., et al. Cytoreductive nephrectomy and exposure to sunitinib—A post hoc analysis of the Immediate Surgery or Surgery after Sunitinib Malate in Treating Patients with Metastatic Kidney Cancer (SURTIME) trial. BJU Int. 2022;130:68–75. doi: 10.1111/bju.15625. PubMed DOI

Meerveld-Eggink A., Graafland N., Wilgenhof S., Van Thienen J.V., Lalezari F., Grant M., Szabados B., Abu-Ghanem Y., Kuusk T., Boleti E., et al. Primary Renal Tumour Response in Patients Treated with Nivolumab and Ipilimumab for Metastatic Renal Cell Carcinoma: Real-world Data Assessment. Eur. Urol. Open. Sci. 2022;35:54–58. doi: 10.1016/j.euros.2021.11.003. PubMed DOI PMC

Chakiryan N.H., Gore L.R., Reich R.R., Dunn R.L., Jiang D.D., Gillis K.A., Green E., Hajiran A., Hugar L., Zemp L., et al. Survival Outcomes Associated with Cytoreductive Nephrectomy in Patients with Metastatic Clear Cell Renal Cell Carcinoma. JAMA Netw. Open. 2022;5:e2212347. doi: 10.1001/jamanetworkopen.2022.12347. PubMed DOI PMC

Labbate C., Hatogai K., Werntz R., Stadler W.M., Steinberg G.D., Eggener S., Sweis R.F. Complete response of renal cell carcinoma vena cava tumor thrombus to neoadjuvant immunotherapy. J. Immunother. Cancer. 2019;7:66. doi: 10.1186/s40425-019-0546-8. PubMed DOI PMC

Pignot G., Thiery-Vuillemin A., Walz J., Lang H., Bigot P., Werle P., Balssa L., Geoffrois L., Leblanc L., Albigès L., et al. Nephrectomy after Complete Response to Immune Checkpoint Inhibitors for Metastatic Renal Cell Carcinoma: A New Surgical Challenge? Eur. Urol. 2020;77:761–763. doi: 10.1016/j.eururo.2019.12.018. PubMed DOI

Kuusk T., Abu-Ghanem Y., Mumtaz F., Powles T., Bex A. Perioperative therapy in renal cancer in the era of immune checkpoint inhibitor therapy. Curr. Opin. Urol. 2021;31:262–269. doi: 10.1097/MOU.0000000000000868. PubMed DOI

Sejima T., Masago T., Yoshida M., Nishi T., Kawabata Y., Tajima Y., Yumioka T., Honda M., Takenaka A. Pathological eradication of recurrent metastatic renal cell carcinoma with sarcomatoid component by nivolumab plus ipilimumab combination therapy. Int. Cancer Conf. J. 2021;10:285–289. doi: 10.1007/s13691-021-00501-2. PubMed DOI PMC

Park J.J., Kellezi O., Hamasha R., Ali A., Alva A.S. Immunotherapy in metastatic sarcomatoid renal cell carcinoma: A single institution experience. Cancer Treat. Res. Commun. 2020;25:100251. doi: 10.1016/j.ctarc.2020.100251. PubMed DOI

The Evolving Landscape of Cytoreductive Nephrectomy in Metastatic Renal Cell Carcinoma