Sarcomatoid Renal Cell Carcinoma: Biology and Treatment Advances - Beyond the Abstract

Sarcomatoid renal cell carcinoma (sRCC) is defined by the differentiation of the typical epithelial cell morphology seen in renal cell carcinoma (RCC) to malignant spindle shaped cells. About 5% of RCC samples contain sRCC components1. It is not a distinct histologic subtype of RCC, but rather occurs in variable proportions with other subtypes of RCC, most commonly with clear cell and chromophobe tumors. sRCC confers an aggressive phenotype and a grade 4 designation by the ISUP grading system2, with a median survival of around 6 months and a suboptimal response to conventional therapies.

Similar protein signatures were noted between sarcomatoid elements and their carcinomatous background in several studies delving into the genetic and molecular basis of sarcomatoid transformation in RCC. This supports the theory of a common cell of origin for these tumors.  However, more mutations in cancer driver genes were noted in the sarcomatoid components, remarkably in tumor protein 53 (TP53)3,4 suggesting a possible culprit gene in the dedifferentiation process. sRCCs over-express both hypoxia inducible factor (HIF) and mammalian target of rapamycin (mTOR) pathway proteins. Joseph et al. found significantly higher expression patterns of PD-1 and PD-L1 in sRCC when compared to ccRCC5.

Nephrectomy is the mainstay of treatment for localized sRCC though with high recurrence rates noted thereafter. Although cytoreductive nephrectomy is becoming standard of care in metastatic RCC, its role in metastatic sRCC has not been adequately investigated. Systemic therapies in sRCC have largely been ineffective. Sarcoma-like cytotoxic chemotherapy regimens have yielded disappointing outcomes. Antiangiogenic  therapies have shown modest benefits, with the combination of cytotoxic and targeted therapies producing better outcomes, as noted in two phase II trials assessing the response to gemcitabine and sunitinib combination therapy6,7. Higher expression of PD-1/PD-L1 in sRCC portends itself to potential therapeutic blockade with PD-1/PD-L1 targeted immunotherapy8. sRCC patients are being included in several clinical trials assessing targeted therapies and immunotherapies in RCC, which will provide valuable knowledge going forward.


Written By: 
Nemer El Mouallem, MD and Asit Paul MD, PhD, Massey Cancer Center, VCU Medical Center, Richmond, Virginia

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References:

  1. Shuch B, Pantuck AJ, Pouliot F, Finley DS, Said JW, Belldegrun AS, et al. Quality of pathological reporting for renal cell cancer: implications for systemic therapy, prognostication and surveillance. BJU Int 2011;108:343-8.
  2. Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM. 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.
  3. Bi M, Zhao S, Said JW, Merino MJ, Adeniran AJ, Xie Z, et al. Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma. Proc Natl Acad Sci U S A 2016;113:2170-5.
  4. Malouf GG, Ali SM, Wang K, Balasubramanian S, Ross JS, Miller VA, et al. Genomic characterization of renal cell carcinoma with sarcomatoid dedifferentiation pinpoints recurrent genomic alterations. Eur Urol 2016;70:348-57.
  5. Joseph RW, Millis SZ, Carballido EM, Bryant D, Gatalica Z, Reddy S, et al. PD-1 and PD-L1 expression in renal cell carcinoma with sarcomatoid differentiation. Cancer Immunol Res 2015;3:1303-07.
  6. Michaelson MD, McKay RR, Werner L, Atkins MB, Van Allen EM, Olivier KM, et al. Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. Cancer 2015;121:3435-43.
  7. Haas NB, Puligandla M, McDermott DF, Dutcher JP, Manola J, Pins M, et al. ECOG 1808: Randomized phase II trial of sunitinib with or without gemcitabine in advanced kidney cancer with sarcomatoid features [abstract 4511]. Presented at the 2016 American Society of Clinical Oncology Annual Meeting, Chicago, Illinois, June 2-6, 2016.
  8. McDermott DF, Sosman JA, Sznol M, Massard C, Gordon MS, Hamid O, et al. Atezolizumab, an anti-programmed death-ligand 1 antibody, in metastatic renal cell carcinoma: long-term safety, clinical activity, and immune correlates from a phase Ia study. J Clin Oncol 2016;34:833-42.
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