Stereotactic radiosurgery for brain metastases from extra-renal clear cell carcinoma: A series of four patients and review of the literature.

Clear cell carcinoma occurring outside of the kidney represents an aggressive histological subtype which is frequently resistant to standard chemotherapy. Brain metastases (BM) from extra-renal clear cell carcinoma (erCCC) are exceedingly rare, and the optimal treatment approach for this histology remains uncertain. To our knowledge, stereotactic radiosurgery (SRS) has not been specifically investigated for this patient population. We performed a retrospective review of patients with erCCC treated with SRS at our institution from 2003 to 2024, identifying 4 cases with a total of 13 BM. Additionally, we conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to summarize prior reports of erCCC BM. The Embase, PubMed/MEDLINE, Scopus, and Web of Science databases were queried for initial identification of records. Gray literature was additionally searched. Baseline patient characteristics, treatment modality, and treatment outcomes were extracted from reports which met inclusion criteria. The median age at initial erCCC diagnosis was 54 years, with an interval to BM ranging from 0 to 3 years. The median lesion diameter was 5.1 mm, with a median size reduction of 52.9 % at the 3-month follow-up. The local control rates were 100 %, 100 %, and 100 % at 6, 12, and 18 months, respectively. Radiation necrosis was detected in a single lesion on 18-month MRI. The mean overall survival (OS) was 23.8 months (SD: 14.5). Twenty items met the inclusion criteria for our review, 19 of which reported a single case of erCCC BM. The majority of erCCC cases were associated with the ovary, followed by those of unknown origin. Among articles reporting the stage of the primary erCCC, 64.3 % were early stage while the remaining 35.7 % were advanced stage. Surgical resection and whole-brain radiotherapy were the most common treatments, with a median OS of 7 months. Genetic characteristics were available for only 2 cases, which identified pathogenic mutations in PIK3CA (p.E545K) or BRCA2 (p.K3326*). Our case series indicates that SRS may be an effective management option for erCCC BM, demonstrating high local control rates and a favorable safety profile. Our systematic review underscores significant variability in treatment outcomes and geographical incidence of this condition, along with existing gaps in genetic characterization and neurosurgical outcomes. Given known differences in clinical behavior between erCCC and other subtypes from the same site of origin, histology-directed treatment strategies may support improved outcomes.