Clinical, pathologic, and molecular profiles of sarcomatoid and rhabdoid differentiated clear cell renal cell carcinoma: A series of 21 tumors.

Clear cell renal cell carcinoma (ccRCC) with sarcomatoid and/or rhabdoid differentiation-distinct dedifferentiation phenotypes-exhibits high aggressiveness and poor prognosis. Despite recent advances, their clinicopathologic and molecular characteristics remain incompletely defined. This study analyzed 21 such cases, predominantly in males (19 patients), with a median age of 64 years (range: 29 - 83 years) and average tumor size of 6.1 cm (range: 3.5 - 14 cm). Among these, 14 cases showed sarcomatoid differentiation, 11 cases exhibited rhabdoid differentiation, and four cases demonstrated both types simultaneously. Most tumors (16/21, 76.19%) exhibited necrosis. Two patients presented with synchronous pulmonary metastases at diagnosis, and six developed distant metastases (bone/lung/liver/brain) 4 - 30 months postoperatively. Next-generation sequencing revealed that 90.5% (19/21) of samples harbored VHL gene alterations, which represent the initial driver mutation in ccRCC development. Additionally, chromatin remodeling genes showed enriched abnormalities, including PBRM1 (52.4%, 11/21), BAP1 (33.3%, 7/21) and SETD2 (19.0%, 4/21), suggesting a potential role for these genes in the transformation to sarcomatoid and/or rhabdoid morphology. Notably, 28.6% of tumors had TSC/MTOR pathway alterations, and TP53 mutations (33.3%) were significantly associated with poor prognosis (p = 0.049). No statistically significant differences in driver mutation prevalence or prognosis were observed between sarcomatoid and rhabdoid differentiation. These findings highlight the value of molecular stratification in elucidating pathogenesis and guiding targeted therapy for this aggressive ccRCC subtype, particularly emphasizing TP53 as a prognostic biomarker and TSC/MTOR alterations as potential therapeutic targets.