Background: Clear cell renal cell carcinoma with rhabdoid features (ccRCC-R) is a highly aggressive variant of renal cell carcinoma that carries a poor prognosis and limited treatment options.Methods: To better define the clinicopathologic and molecular landscape of ccRCC-R, we conducted an integrated clinicopathologic and molecular study of 17 tumors of ccRCC-R, utilizing comprehensive histomorphologic evaluation, immunohistochemistry, and targeted next-generation sequencing (NGS).Results: Histologically, all tumors demonstrated classic clear cell renal cell carcinoma morphology with focal to extensive rhabdoid differentiation, characterized by eccentrically located nuclei, prominent nucleoli, abundant eosinophilic cytoplasm, and paranuclear intracytoplasmic inclusion. Architectural alterations, including solid/sheet-like, alveolar/trabecular, and pseudopapillary growth patterns, were frequently observed. Immunohistochemically, tumors commonly exhibited loss of PAX8 and Claudin4 expression, preserved cytokeratin AE1/AE3 staining, and diffuse membranous CAIX expression. Frequent loss of SMARCA2 with retained SMARCA4 supported aberrations in chromatin remodeling. Unsupervised hierarchical clustering based on pathway-specific somatic mutations identified four distinct molecular subgroups defined by recurrent alterations in (1) DNA damage repair (DDR) genes, (2) chromatin remodeling genes, (3) PI3K/AKT/mTOR signaling components, and (4) MAPK pathway genes. Clinicopathologic correlation revealed that each subgroup was associated with unique biological characteristics and suggested distinct therapeutic vulnerabilities.Conclusions: Our findings underscore the molecular heterogeneity of ccRCC-R and support the utility of pathway-based stratification for guiding precision oncology approaches and biomarker-informed clinical trial design.
背景：具有横纹肌样特征的透明细胞肾细胞癌（ccRCC-R）是一种高度侵袭性的肾细胞癌亚型，预后较差且治疗选择有限。方法：为更明确ccRCC-R的临床病理与分子特征，我们对17例ccRCC-R肿瘤进行了整合性临床病理与分子研究，采用全面的组织形态学评估、免疫组织化学及靶向二代测序技术。结果：组织学上所有肿瘤均呈现经典透明细胞肾细胞癌形态，伴局灶至广泛横纹肌样分化，特征包括偏心性细胞核、显著核仁、丰富嗜酸性胞质及核旁胞质内包涵体。结构改变（如实性/片状、腺泡状/小梁状及假乳头状生长模式）常见。免疫组化显示肿瘤普遍存在PAX8与Claudin4表达缺失，细胞角蛋白AE1/AE3表达保留，以及弥漫性膜CAIX表达。SMARCA2频繁缺失伴SMARCA4保留支持染色质重塑异常。基于通路特异性体细胞突变的非监督层次聚类分析，识别出四个分子亚组，分别由以下基因的反复突变定义：（1）DNA损伤修复基因，（2）染色质重塑基因，（3）PI3K/AKT/mTOR信号通路组分，（4）MAPK通路基因。临床病理关联分析显示各亚组具有独特的生物学特征，并提示差异化的治疗脆弱性。结论：本研究揭示了ccRCC-R的分子异质性，支持基于通路的分层策略对指导精准肿瘤治疗及生物标志物导向的临床试验设计具有重要价值。
肿瘤(癌症)患者之家