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Sarcomatoid renal cell carcinoma: biology, natural history and management

Nature Reviews Urology volume 17, pages 659–678 (2020)Cite this article

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Abstract

Sarcomatoid dedifferentiation is an uncommon feature that can occur in most histological subtypes of renal cell carcinomas (RCCs) and carries a decidedly poor prognosis. Historically, conventional treatments for sarcomatoid RCCs (sRCCs) have shown little efficacy, and median survival is commonly 6–13 months. Despite being first described in 1968, the mechanisms driving sarcomatoid dedifferentiation remain poorly understood, and information and treatment options available to physicians and patients are limited. When diagnosed at an early stage, surgical intervention remains the treatment of choice. However, preoperative identification through routine imaging or biopsy is unreliable and most patients present with advanced disease and systemic symptoms. For these patients, the role of cytoreductive nephrectomy is disputed. The expansion of immunotherapies approved for RCCs has generated a search for biomarkers that might be indicative of treatment response in sRCCs, although a proven effective systemic agent remains elusive. PDL1 expression is increased in sarcomatoid dedifferentiated renal tumours, which suggests that patients with sRCCs could benefit from PD1 and/or PDL1 immune checkpoint blockade therapy. Treatment outcomes for sarcomatoid tumours have remained relatively consistent compared with other RCCs, but further investigation of the tumour–immune cell microenvironment might yield insights into further therapeutic possibilities.

Key Points

  • Sarcomatoid dedifferentiation is not considered to be a unique histological subtype of renal cell carcinomas (RCCs); rather, it can be present within any subtype of RCCs.

  • Sarcomatoid dedifferentiation appears in ~4% of all RCCs, but is present in ~20% of all metastatic RCCs. According to WHO guidelines, any RCC with sarcomatoid dedifferentiation is a WHO–International Society of Urological Pathology grade 4 lesion.

  • Sarcomatoid dedifferentiation is often heterogeneously present within RCCs, making routine imaging and biopsy unreliable for preoperative detection. Surgical resection for localized disease is the standard of care, with subsequent close monitoring of patients following surgery.

  • In patients with metastatic disease, conventional therapies such as surgery and systemic agents have been ineffective and overall 5-year survival remains at 23.5–33%.

  • Previous genomic analyses have failed to identify definitive mutational drivers of disease. However, sarcomatoid RCCs (sRCCs) have been shown to have higher PD1 and PDL1 expression than other subtypes of RCCs. Newer combinations of immune checkpoint inhibitor immunotherapies could yield improved responses and outcomes.

  • Studies investigating sRCCs are limited by patient numbers owing to the low incidence of sRCCs and their advanced stage at presentation. Multi-institutional efforts to establish a consensus on treatment recommendations based on highly powered data are essential.

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Fig. 1: Gross sections of an sRCC after radical nephrectomy.
Fig. 2: Histopathology of sRCC.
Fig. 3: Signalling pathways involved in EMT reported in sRCC.
Fig. 4: PDL1 expression in sRCC.

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  1. These authors contributed equally: Jose A. Karam, A. Ari Hakimi

Authors and Affiliations

  1. Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Kyle A. Blum, Paul Russo & A. Ari Hakimi

  2. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Sounak Gupta & Satish K. Tickoo

  3. Department of Radiation Oncology, Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Timothy A. Chan

  4. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Robert J. Motzer

  5. Departments of Urology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Jose A. Karam

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K.A.B. researched data for the article. K.A.B., S.G., J.A.K. and A.A.H. wrote the article. All authors made substantial contributions to discussion of the content and reviewed/edited the manuscript before submission.

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J.A.K. is a member of consulting or advisory boards for, and has received honoraria from, Merck, EMD Serono, Genentech, Novartis and Pfizer. J.A.K. has received institutional research funding from Merck, Genentech and Mirati. R.J.M. has received grants and paid consultancy from Eisai, Exelixis, Genentech, Roche, Novartis, Merck and Pfizer, paid consultancy from Astra Zeneca and grants from Bristol Myers Squibb. All other authors declare no competing interests.

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Blum, K.A., Gupta, S., Tickoo, S.K. et al. Sarcomatoid renal cell carcinoma: biology, natural history and management. Nat Rev Urol 17, 659–678 (2020). https://doi.org/10.1038/s41585-020-00382-9

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