Department of Pathology, Genitourinary Pathology Center of Excellence, University of Pittsburgh Medical Center, Pittsburgh, USA.
Department of Pathology, Genitourinary Pathology Center of Excellence, University of Pittsburgh Medical Center, Pittsburgh, USA.
Ann Diagn Pathol. 2024 Feb;68:152223. doi: 10.1016/j.anndiagpath.2023.152223. Epub 2023 Nov 4.
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.
SET 结构域包含蛋白 2（SETD2）和 BRCA1 相关蛋白 1（BAP1）都是染色质重塑基因，常发生突变的 clear cell renal cell carcinoma（ccRCC），并参与肿瘤的进展和转移。在此，我们研究了 7 例局部晚期 ccRCC 中单独 SETD2 突变的临床病理特征，并与 7 例局部晚期 ccRCC 中单独 BAP1 突变的病例进行了比较。SETD2 突变的 ccRCC 表现为高级别转化，包括体积增大的肿瘤细胞，具有丰富的透明细胞质、增大的不规则核，有明显的核仁、嗜酸性细胞质颗粒，排列在各种结构模式中，如大巢状、管状、管状乳头和实性。71%（5/7 例）的 SETD2 突变的 ccRCC 表现出横纹肌样形态。SETD2 突变的 ccRCC 具有明显的侵袭性生长倾向；所有病例均有血管侵犯和肾周（包膜外）脂肪组织侵犯。肾切除术后，67%（4/7 例）的 SETD2 突变的 ccRCC 患者发现远处转移。最常见的转移部位是肺（3 例），其次是腔静脉前淋巴结（1 例）。BAP1 突变的 ccRCC 也表现出相似的高级别形态，具有横纹肌样和/或肉瘤样特征。它们的高级别特征与 SETD2 突变的 ccRCC 大多重叠，这使得仅从形态上难以预测 BAP1 或 SETD2 突变的存在。这些发现证明了使用分子检测来检测这些突变的合理性，尤其是在遇到高级别 ccRCC 时。在 ccRCC 中检测 SETD2 和 BAP1 突变有助于分层风险和制定适当的治疗策略。
