Sarcomatoid-variant represents a spindle cell phenotype of renal cell carcinoma (RCC) that can be present in any subtype (clear cell, papillary, chromophobe or unclassified). Case reports of sarcomatoid-variant RCC highlight a poor prognosis. Most reports comprise less than 20 patients, and lack consensus on treatment outcome and an optimal approach to management.1–8
The reported median survival from initial diagnosis ranges from 9 to 19 months.9,10
Response rates to chemotherapy and cytokines are low across all series.1–3,11
Recent years have brought significant advances in classification and treatment options for metastatic RCC. An improved understanding of the mechanisms involved in RCC growth and angiogenesis has led to the development and implementation of antiangiogenesis-targeted therapies in the treatment paradigm for metastatic RCC. Small molecule-targeted inhibitors sunitinib, sorafenib, temsirolimus, everolimus, and the monoclonal antibody bevacizumab have shown substantial antitumor activity in randomized phase 3 clinical trials,12–17
and have assumed a predominant role in the standard management of first-line, second-line, and third-line treatment for metastatic clear-cell RCC. As a result, the treatment paradigm, prognosis, and overall survival (OS) for patients with metastatic RCC have dramatically improved.
These new agents target angiogenesis by the hypoxia-driven gene pathway, with differences in the targeting profile, mechanisms of action, and pharmacokinetic profiles. For example, sunitinib is a small molecule that blocks activity for the receptors of vascular endothelial growth factor and platelet-derived growth factor, presumably of the endothelium. In contrast, temsirolimus, an mTOR inhibitor, may perform a more central action in tumor cells and endothelium by inhibiting multiple functions, including regulation of cell growth, metabolism, and angiogenesis.
In this era of targeted therapy, individualized care is an important goal in the treatment of RCC. The identification of subsets of patients who may or may not benefit from these agents is of critical importance. With the exception of the temsirolimus phase 3 trial,13
which included any RCC histology, other pivotal phase 3 trials conducted with targeted agents, and formerly with cytokines, provided a limited characterization of RCC histology, or focused primarily on the clear-cell component. In addition, none of these trials included a central pathology review or specified the presence of sarcomatoid features in the tumors. Studies characterizing histology and immunohistochemical (IHC) expression are necessary to identify subsets of patients who either respond or are refractory to treatment, and this information can be used to direct specific drug therapy and guide clinical trial eligibility and design.
Overall, experience with these new, targeted agents is very limited in sarcomatoid-variant RCC, a rare and aggressive RCC tumor type. Nanus et al5
reported antitumor activity in several patients with sarcomatoid-variant RCC who had been treated with the combination of doxorubicin and gemcitabine chemotherapy. This led to an Eastern Cooperative Oncology Group phase 2 trial to formally study the regimen.18
More recently, a retrospective analysis reported objective responses to vascular endothelial growth factor therapy for sarcomatoid-variant RCC, and concluded that these agents were of value in treating this subset of patients.19
On account of the activity observed in this report,19
and earlier studies showing mixed success with chemotherapy and cytokines, we carried out a retrospective analysis on all patients with sarcomatoid-variant metastatic RCC treated at Memorial Sloan-Kettering Cancer Center (MSKCC) over an 11-year interval. This report covers clinical features, treatment outcomes, and survival for patients with sarcomatoid-variant RCC. In addition, we investigated the IHC expression profile of hypoxia-inducible and mTOR pathway markers in patients with tumor specimens available for review.