Trends and outcomes in localized renal cell carcinoma with sarcomatoid dedifferentiation: Analysis of the National Cancer Database.
Authors: Wang Luke , Puri Dhruv , Javier-Desloges Juan , Dhanji Sohail , Liu Franklin , Afari Jonathan , Meagher Margaret , Nguyen Mimi , Hakimi Kevin , Ghassemzadeh Saeed , Shah Aastha , Murphy James Don , McKay Rana R. , Derweesh Ithaar H 
Published: March 2023

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Background: Sarcomatoid dedifferentiation in Renal Cell Carcinoma (sRCC) is well known to be a subtype with poor prognosis with a high rate of synchronous metastases at presentation. Nonetheless, outcomes in a contemporary cohort of patients with localized sRCC are not well characterized in a population-based study. We sought to determine the clinical characteristics, temporal trends in prevalence, and survival outcomes in patients with localized sarcomatoid RCC. Methods: From 2004-2019, all 440,230 cases of RCC in patients ≥18 years were extracted from the National Cancer Database; of these, 3.3% (14,713) had sarcomatoid dedifferentiation. Trend analyses were conducted using Cochran-Armitage test of trend. Multivariable Cox Proportional-Hazards regression was used to determine the impact of clinical and pathologic characteristics on all cause mortality (ACM) in patients with non-metastatic sRCC. Actuarial Overall Survival (OS) was computed with Kaplan-Meier analysis (KMA), with sub-analysis performed for patients with AJCC Prognostic Stages I-III (Stage). Clear cell was reference histology for all analyses. Holm adjustment for multiple comparisons was applied when necessary. Results: Sarcomatoid dedifferentiation increased from 1.9% in 2004 to 4.1% in 2019, average annual percentage change (AAPC) 0.060 (p<0.001). sRCC with synchronous metastasis decreased from 48.7% in 2004 to 38.7% in 2019, AAPC -0.028 (p<0.001). Of all sRCC, 39.3% had synchronous metastasis to lung, 17.9% to bone, 5.3% to liver, 2.2% to brain, 35.3% to >1 site. On Cox regression for non-metastatic sRCC, ACM was associated with age (HR 1.02, p<0.001), Charlson comorbidity (HR 1.21, p<0.001), tumor size (HR 1.04, p<0.001), cN1 (HR 1.01, p<0.001), collecting duct (HR 2.33, p=0.002), medullary (HR 4.75, p=0.031), and RCC unspecified (HR 1.46, p<0.001) histology, tumor grade (HR 1.30, p<0.001); and inversely with partial (HR 0.19, p<0.001) and radical (HR 0.32, p<0.001) nephrectomy. In non-metastatic sRCC, 5-year OS was 52.9%. Substratification showed 5-year OS of 72.9% for Stage I, 60.4% Stage II, and 40.9% for Stage III sRCC (p<0.001). Conclusions: The findings constitute the largest retrospective characterization of localized RCC with sarcomatoid dedifferentiation; sRCC has increased in prevalence, while patients presenting with synchronous metastases have decreased. Despite the latter trend, outcomes in patients with localized sRCC are poor and associated with patient comorbidity, stage, and associated histological findings. While partial and radical nephrectomy was associated with improved outcomes, these findings must be interpreted with caution and are likely secondary to significant selection bias. Future studies investigating the underlying biology driving increased sarcomatoid dedifferentiation despite generalized downward stage migration in RCC are requisite.