Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Mod Pathol. 2022 Mar;35(3):333-343. doi: 10.1038/s41379-021-00896-6. Epub 2021 Sep 20.
Low-grade oncocytic tumor (LOT) of the kidney is a recently described entity with poorly understood pathogenesis. Using next-generation sequencing (NGS) and complementary approaches, we provide insight into its biology. We describe 22 LOT corresponding to 7 patients presenting with a median age of 75 years (range 63-86 years) and male to female ratio 2:5. All 22 tumors demonstrated prototypical microscopic features. Tumors were well-circumscribed and solid. They were composed of sheets of tumor cells in compact nests. Tumor cells had eosinophilic cytoplasm, round to oval nuclei (without nuclear membrane irregularities), focal subtle perinuclear halos, and occasional binucleation. Sharply delineated edematous stromal islands were often observed. Tumor cells were positive for PAX8, negative for CD117, and exhibited diffuse and strong cytokeratin-7 expression. Six patients presented with pT1 tumors. At a median follow-up of 29 months, four patients were alive without recurrence (three patients had died from unrelated causes). All tumors were originally classified as chromophobe renal cell carcinoma, eosinophilic variant (chRCC-eo). While none of the patients presented with known syndromic features, one patient with multiple bilateral LOTs was subsequently found to have a likely pathogenic germline TSC1 mutation. Somatic, likely activating, mutations in MTOR and RHEB were identified in all other evaluable LOTs. As assessed by phospho-S6 and phospho-4E-BP1, mTOR complex 1 (mTORC1) was activated across all cases but to different extent. MTOR mutant LOT exhibited lower levels of mTORC1 activation, possibly related to mTORC1 dimerization and the preservation of a wild-type MTOR copy (retained chromosome 1). Supporting its distinction from related entities, gene expression analyses showed that LOT clustered separately from classic chRCC, chRCC-eo, and RO. In summary, converging mTORC1 pathway mutations, mTORC1 complex activation, and a distinctive gene expression signature along with characteristic phenotypic features support LOT designation as a distinct entity with both syndromic and non-syndromic cases associated with an indolent course.
低级别嗜酸细胞瘤（LOT）是一种新近描述的实体瘤，其发病机制尚不清楚。我们使用下一代测序（NGS）和互补方法深入了解其生物学特性。我们描述了 7 名患者的 22 例 LOT，中位年龄为 75 岁（范围 63-86 岁），男女比例为 2:5。所有 22 例肿瘤均表现出典型的显微镜特征。肿瘤边界清楚，呈实性。它们由肿瘤细胞的片状紧密巢组成。肿瘤细胞具有嗜酸性细胞质、圆形至椭圆形细胞核（无核膜不规则）、局灶性细微的核周晕、偶尔双核。常观察到锐利界定的水肿性基质岛。肿瘤细胞对 PAX8 呈阳性，对 CD117 呈阴性，并且 CK7 弥漫且强烈表达。6 名患者表现为 pT1 肿瘤。中位随访 29 个月时，4 名患者无复发且存活（3 名患者死于其他原因）。所有肿瘤最初均归类为嗜酸细胞型肾嫌色细胞癌（chRCC-eo）。虽然没有患者出现已知的综合征特征，但一名患有多发双侧 LOT 的患者随后发现可能存在致病性 TSC1 种系突变。所有可评估的 LOT 均存在 MTOR 和 RHEB 的体细胞、可能激活的突变。所有病例均通过磷酸化 S6 和磷酸化 4E-BP1 评估 mTORC1 激活，但程度不同。MTOR 突变 LOT 表现出较低水平的 mTORC1 激活，可能与 mTORC1 二聚化和保留野生型 MTOR 拷贝（保留染色体 1）有关。支持其与相关实体的区别，基因表达分析显示 LOT 与经典 chRCC、chRCC-eo 和 RO 聚类分开。总之， converging mTORC1 通路突变、mTORC1 复合物激活以及独特的基因表达特征以及特征性表型特征支持 LOT 作为一种具有综合征和非综合征病例的独特实体的指定，这些病例与惰性病程相关。
