Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

The treatment approach to non-clear cell renal carcinoma

Toni K Choueiri, MD
Sumanta K Pal, MD
Section Editor
Michael B Atkins, MD
Deputy Editor
Michael E Ross, MD


Although many advances have been made in the treatment of metastatic renal cell carcinoma (RCC), the majority of studies to date have been limited to patients with a component of clear cell disease [1]. Due to the infrequency of non-clear cell RCC, there is a paucity of high-quality data to help inform the management of these tumors.

This topic will discuss the management of non-clear cell RCC. The epidemiology, pathology, and pathogenesis of these tumors are discussed separately, as is the treatment of clear cell RCC. (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma" and "Overview of the treatment of renal cell carcinoma".)


Non-clear cell renal cell carcinomas (RCCs) are characterized by morphology, growth pattern, cell of origin, and where it is known, by the histochemical and biologic bases that underlie the different types of tumors. The main subtypes of non-clear cell RCC include (see "Epidemiology, pathology, and pathogenesis of renal cell carcinoma", section on 'Pathology'):



To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Jul 18, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Pal SK, Choueiri TK. Systemic Therapies for Metastatic Renal Cell Carcinoma of Variant Histology. In: Renal Cell Carcinoma, Tannir NM (Ed), Oxford American Oncology Library, New York 2014.
  2. Zisman A, Chao DH, Pantuck AJ, et al. Unclassified renal cell carcinoma: clinical features and prognostic impact of a new histological subtype. J Urol 2002; 168:950.
  3. Coogan CL, McKiel CF Jr, Flanagan MJ, et al. Renal medullary carcinoma in patients with sickle cell trait. Urology 1998; 51:1049.
  4. Gupta R, Billis A, Shah RB, et al. Carcinoma of the collecting ducts of Bellini and renal medullary carcinoma: clinicopathologic analysis of 52 cases of rare aggressive subtypes of renal cell carcinoma with a focus on their interrelationship. Am J Surg Pathol 2012; 36:1265.
  5. WHO classification of tumours of the urinary system and male genital organs, Moch H, Humphrey PA, Ulbright TM, Reuter VE (Eds), World Health Organization, Lyon 2016.
  6. Motzer RJ, Bacik J, Mariani T, et al. Treatment outcome and survival associated with metastatic renal cell carcinoma of non-clear-cell histology. J Clin Oncol 2002; 20:2376.
  7. Bylow KA, Atkins MB, Posadas EM, et al. Phase II trial of carboplatin and paclitaxel in papillary renal cell carcinoma. Clin Genitourin Cancer 2009; 7:39.
  8. Ronnen EA, Kondagunta GV, Ishill N, et al. Treatment outcome for metastatic papillary renal cell carcinoma patients. Cancer 2006; 107:2617.
  9. Vera-Badillo FE, Templeton AJ, Duran I, et al. Systemic therapy for non-clear cell renal cell carcinomas: a systematic review and meta-analysis. Eur Urol 2015; 67:740.
  10. Upton MP, Parker RA, Youmans A, et al. Histologic predictors of renal cell carcinoma response to interleukin-2-based therapy. J Immunother 2005; 28:488.
  11. Haas NB, Lin X, Manola J, et al. A phase II trial of doxorubicin and gemcitabine in renal cell carcinoma with sarcomatoid features: ECOG 8802. Med Oncol 2012; 29:761.
  12. Gollob JA, Upton MP, DeWolf WC, Atkins MB. Long-term remission in a patient with metastatic collecting duct carcinoma treated with taxol/carboplatin and surgery. Urology 2001; 58:1058.
  13. Milowsky MI, Rosmarin A, Tickoo SK, et al. Active chemotherapy for collecting duct carcinoma of the kidney: a case report and review of the literature. Cancer 2002; 94:111.
  14. Peyromaure M, Thiounn N, Scotté F, et al. Collecting duct carcinoma of the kidney: a clinicopathological study of 9 cases. J Urol 2003; 170:1138.
  15. Oudard S, Banu E, Vieillefond A, et al. Prospective multicenter phase II study of gemcitabine plus platinum salt for metastatic collecting duct carcinoma: results of a GETUG (Groupe d'Etudes des Tumeurs Uro-Génitales) study. J Urol 2007; 177:1698.
  16. Strouse JJ, Spevak M, Mack AK, et al. Significant responses to platinum-based chemotherapy in renal medullary carcinoma. Pediatr Blood Cancer 2005; 44:407.
  17. Walsh A, Kelly DR, Vaid YN, et al. Complete response to carboplatin, gemcitabine, and paclitaxel in a patient with advanced metastatic renal medullary carcinoma. Pediatr Blood Cancer 2010; 55:1217.
  18. Schaeffer EM, Guzzo TJ, Furge KA, et al. Renal medullary carcinoma: molecular, pathological and clinical evidence for treatment with topoisomerase-inhibiting therapy. BJU Int 2010; 106:62.
  19. Kondagunta GV, Drucker B, Schwartz L, et al. Phase II trial of bortezomib for patients with advanced renal cell carcinoma. J Clin Oncol 2004; 22:3720.
  20. Ronnen EA, Kondagunta GV, Motzer RJ. Medullary renal cell carcinoma and response to therapy with bortezomib. J Clin Oncol 2006; 24:e14.
  21. Escudier B, Droz JP, Rolland F, et al. Doxorubicin and ifosfamide in patients with metastatic sarcomatoid renal cell carcinoma: a phase II study of the Genitourinary Group of the French Federation of Cancer Centers. J Urol 2002; 168:959.
  22. Armstrong AJ, Halabi S, Eisen T, et al. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol 2016.
  23. Tannir NM, Jonasch E, Albiges L, et al. Everolimus Versus Sunitinib Prospective Evaluation in Metastatic Non–Clear Cell Renal Cell Carcinoma (ESPN): A Randomized Multicenter Phase 2 Trial. Eur Urol 2015.
  24. Motzer RJ, Barrios CH, Kim TM, et al. Record-3: Phase II randomized trial comparing sequential first-line everolimus (EVE) and second-line sunitinib (SUN) versus first-line SUN and second-line EVE in patients with metastatic renal cell carcinoma (mRCC). ASCO Meeting Abstracts 2013; 31:4504.
  25. Irshad T, Olencki T, Zynger L, et al. Bevacizumab in metastatic papillary renal cell carcinoma (PRCC). J Clin Oncol 29: 2011 (suppl; abstr e15158)
  26. Armstrong AJ, Broderick S, Eisen T, et al. Final clinical results of a randomized phase II international trial of everolimus vs. sunitinib in patients with metastatic non-clear cell renal cell carcinoma (ASPEN). J Clin Oncol 33, 2015 (suppl; abstr 4507).
  27. Escudier B, Molinie V, Bracarda S, et al. Open-label phase 2 trial of first-line everolimus monotherapy in patients with papillary metastatic renal cell carcinoma: RAPTOR final analysis. Eur J Cancer 2016; 69:226.
  28. Ravaud A, Oudard S, De Fromont M, et al. First-line treatment with sunitinib for type 1 and type 2 locally advanced or metastatic papillary renal cell carcinoma: a phase II study (SUPAP) by the French Genitourinary Group (GETUG)†. Ann Oncol 2015; 26:1123.
  29. Stamatakis L, Singer EA, Siddiqui MM, et al. Phase II trial of bevacizumab and erlotinib in patients with advanced hereditary leiomyomatosis and renal cell cancer (HLRCC) or sporadic papillary renal cell carcinoma. Eur J Cancer 2011:Abstr 2753.
  30. Srinivasan R, et al. Mechanism based targeted therapy for hereditary leimyomatosis and renal cell cancer and sporadic papillary renal cell carcinoma: interim results from a phase 2 study of bevacizumab and erlotinib (abstract 5). EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (2014).
  31. Choueiri TK, Vaishampayan U, Rosenberg JE, et al. Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma. J Clin Oncol 2013; 31:181.
  32. Choueiri TK, Plimack E, Arkenau HT, et al. Biomarker-Based Phase II Trial of Savolitinib in Patients With Advanced Papillary Renal Cell Cancer. J Clin Oncol 2017; 35:2993.
  33. 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.
  34. Chittoria N, Zhu H, Choueiri TK, et al. Outcome of metastatic sarcomatoid renal cell carcinoma (sRCC): Results from the International mRCC Database Consortium. ASCO Meeting Abstracts 2013; 31:4565.
  35. Michaelson MD, McDermott DF, Atkins MB, et al. Combination of antiangiogenic therapy and cytotoxic chemotherapy for sarcomatoid renal cell carcinoma. ASCO Meeting Abstracts 2013; 31:4512.
  36. NCT01164228: A Randomized Phase II Trial of Sunitinib/Gemcitabine or Sunitinib in Advanced Renal Cell Carcinoma With Sarcomatoid Features http://www.clinicaltrials.gov (Accessed on March 19, 2013).
  37. Tannir NM, Plimack E, Ng C, et al. A phase 2 trial of sunitinib in patients with advanced non-clear cell renal cell carcinoma. Eur Urol 2012; 62:1013.
  38. Choueiri TK, Plantade A, Elson P, et al. Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. J Clin Oncol 2008; 26:127.
  39. Pécuchet N, Bigot F, Gachet J, et al. Triple combination of bevacizumab, gemcitabine and platinum salt in metastatic collecting duct carcinoma. Ann Oncol 2013; 24:2963.
  40. Hakimi AA, Koi PT, Milhoua PM, et al. Renal medullary carcinoma: the Bronx experience. Urology 2007; 70:878.
  41. Maroja Silvino MC, Venchiarutti Moniz CM, Munhoz Piotto GH, et al. Renal medullary carcinoma response to chemotherapy: a referral center experience in Brazil. Rare Tumors 2013; 5:e44.
  42. Choueiri TK, Lim ZD, Hirsch MS, et al. Vascular endothelial growth factor-targeted therapy for the treatment of adult metastatic Xp11.2 translocation renal cell carcinoma. Cancer 2010; 116:5219.
  43. Malouf GG, Camparo P, Oudard S, et al. Targeted agents in metastatic Xp11 translocation/TFE3 gene fusion renal cell carcinoma (RCC): a report from the Juvenile RCC Network. Ann Oncol 2010; 21:1834.
  44. Choueiri TK, Fay AP, Gray KP, et al. PD-L1 expression in nonclear-cell renal cell carcinoma. Ann Oncol 2014; 25:2178.
  45. Geynisman DM. Anti-programmed Cell Death Protein 1 (PD-1) Antibody Nivolumab Leads to a Dramatic and Rapid Response in Papillary Renal Cell Carcinoma with Sarcomatoid and Rhabdoid Features. Eur Urol 2015; 68:912.
  46. Klatte T, Pantuck AJ, Said JW, et al. Cytogenetic and molecular tumor profiling for type 1 and type 2 papillary renal cell carcinoma. Clin Cancer Res 2009; 15:1162.