From the genetic standpoint, we have found that smrRCC is genetically distinct from conventional clear cell RCC (ccRCC) as it shows no observed loss of chromosome 3p. In our cohort, somatic VHL variants were only observed in two tumors, suggesting that VHL loss may not be the primary driver in these tumors. Previous studies have highlighted pathogenic variants in the genes associated with the PI3K/Akt/mTOR pathway, including TSC1, TSC2, and MTOR.3 Similar to other authors, we observed pathogenic variants in MTOR and PIK3CA in two separate smrRCC tumors in two different patients. Furthermore, Liu et al.4 proposed that variants of ASXL1 in smrRCC may result in upregulation of the PI3K/Akt/mTOR pathway. Although no pathogenic ASXL1 variants were observed in our cohort, 8 of 26 patients (30.7%) possessed a germline variant of unknown significance in ASXL1. These ASXL1 germline variants are predicted to be benign or likely benign, but seem to be enriched in this cohort compared to the general population. These observations demonstrate the possibility that germline ASXL1 variants might increase the risk of smrRCC.
From a clinical standpoint, 88.5% of patients presented with bilateral multifocal (BMF) renal masses. The median age at initial renal surgery was 60 years. The cohort included 19 (73.1%) males and 19 (73.1%) patients identified as Black/African American. Across the cohort, patients underwent a cumulative 48 renal surgeries; 1 (3.8%) patient required bilateral radical nephrectomies after previously undergoing bilateral partial nephrectomies. Patients with smrRCC can also have different tumor histology; of the 216 total tumors resected from our cohort, 171 (79.2%) demonstrated smrRCC histology, while the next most common was ccRCC.
smrRCC has generally been described as an indolent tumor with a favorable prognosis.5 The majority of smrRCC tumors present with ISUP/Fuhrman grade 1-2, though in our cohort, we found a subset of tumors with ISUP/Fuhrman grade 3-4. We found that smrRCC is not uniformly low risk; specifically, one patient, after undergoing bilateral renal surgery for stage pT3a and pT1b smrRCC, developed pulmonary metastasis confirmed to originate from an ISUP grade 3 and pT3a smrRCC tumor. This case suggests that smrRCC has metastatic potential, with pathologic grade and stage mainly influencing oncologic behavior and risk of metastasis.
At our institution, we manage this group of patients similarly to individuals with BMF disease, as they frequently present with bilateral and multifocal masses. All patients undergo germline genetic testing as well as somatic testing of their tumors. They receive periodic MRI surveillance to assess tumor growth, and intervention is recommended when the largest lesion reaches 3 cm. Partial nephrectomy is the preferred surgical approach whenever feasible, although the final decision depends on the patient’s clinical status and the anatomic complexity of the tumors. Follow-up after tumor removal is influenced by grade and stage at surgery. When treating patients with smrRCC, urologists should recognize that multiple renal interventions may be required over time, and efforts should be made to prioritize nephron-sparing approaches.
In conclusion, smrRCC often presents with BMF disease, often requiring multiple surgeries. Additionally, in our cohort, we saw a high proportion of Black/African American and male patients. Genetic evaluation suggests that certain molecular pathways might drive the development of smrRCC and offer the possibility that germline ASXL1 variants might increase the risk of this tumor type. Most smrRCC tumors are low grade, though our findings suggest that pathologic grade and stage may influence oncologic behavior and metastatic potential. Intervention extent and timing should be optimized to mitigate the cumulative impact of repeated renal surgeries, preserve renal function, and balance the oncological risk.
Funding:
This research was supported by the Intramural Research Program of the National Institutes of Health (NIH). The contributions of the NIH authors were made as part of their official duties as NIH federal employees, are in compliance with agency policy requirements, and are considered Works of the United States Government. However, the findings and conclusions presented in this paper are those of the authors and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services.
Written by: Ruben Blachman-Braun, Lauren Loebach, Braden Millan, Mark W. Ball
- Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
- Blachman-Braun R, Patel MH, Millan B, et al. Unraveling Smooth Muscle-Rich Renal Cell Carcinoma: Clinical, Oncological, Genetic, and Pathological Insights. Urology. Published online November 17, 2025. doi:10.1016/j.urology.2025.11.234
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- Badoiu SC, Greabu M, Miricescu D, et al. PI3K/AKT/mTOR Dysregulation and Reprogramming Metabolic Pathways in Renal Cancer: Crosstalk with the VHL/HIF Axis. Int J Mol Sci. May 7 2023;24(9).
- Liu Y, Zhou L, Xu H, et al. Mutated ASXL1 upregulates mTOR expression in renal cell carcinoma with fibromyomatous stroma. Virchows Arch. Aug 2024;485(2):379-382.
- Yeh YA, Constantinescu M, Chaudoir C, et al. Renal cell carcinoma with leiomyomatous stroma: a review of an emerging entity distinct from clear cell conventional renal cell carcinoma. Am J Clin Exp Urol. 2019;7(5):321-326.