Morphological characteristics of SETD2-mutated locally advanced clear cell renal cell carcinoma: Comparison with BAP1-mutated clear cell renal cell carcinoma

• Published in: Annals of diagnostic pathology Vol. 68; p. 152223
• Main Authors: Takeda, Kotaro, Bastacky, Sheldon, Dhir, Rajiv, Mohebnasab, Maedeh, Quiroga-Garza, Gabriela M
• Format: Journal Article
• Language: English
• Published: United States 01-02-2024
• Subjects: High-grade; SETD2; Clear cell renal cell carcinoma; Gene mutation; BAP1
• ISSN: 1092-9134; 1532-8198
• DOI: 10.1016/j.anndiagpath.2023.152223

SET-domain containing 2 (SETD2) and BRCA1-associated protein 1 (BAP1), both chromatin remodeling genes, are frequently mutated in clear cell renal cell carcinoma (ccRCC) and involved in tumor progression and metastasis. Herein, we studied clinicopathologic features of 7 cases of locally advanced ccRCC with single SETD2 mutation, and compared to 7 cases of locally advanced ccRCC with single BAP1 mutation. SETD2-mutated ccRCC showed high-grade transformation, comprising of enlarged tumor cells with voluminous clear cytoplasm, enlarged irregular nuclei with prominent nucleoli, eosinophilic cytoplasmic granules, arranged in various architectural patterns such as large nested, tubular, tubulopapillary and solid. 71 % (5 of 7 cases) of SETD2-mutated ccRCC showed a rhabdoid morphology. SETD2-mutated ccRCC have striking propensity for invasive growth; all cases have vascular invasion and perirenal (extracapsular) adipose tissue invasion. After nephrectomy, distant metastasis was found in 67 % (4 of 7 cases) of patients with SETD2-mutated ccRCC. The most common metastatic site was the lung (3 cases), followed by precaval lymph nodes (1 case). BAP1-mutated ccRCC also showed a similar high-grade morphology, with rhabdoid and/or sarcomatoid features. Their high-grade features mostly overlapped with those of SETD2-mutated ccRCC, which makes difficult to predict the presence of BAP1 or SETD2 mutation solely from morphology. These findings justify the use of molecular testing to detect these mutations, especially when we encounter high-grade ccRCC. Detecting SETD2 and BAP1 mutation in ccRCC is useful for risk stratification and proper therapeutic strategy.