Medical Pole of Biology and Pathology, Hospices Civils de Lyon, Centre hospitalier Lyon Sud, Pierre Bénite, France.
Medical Pole of Biology and Pathology, Hospices Civils de Lyon, Centre hospitalier Lyon Sud, Pierre Bénite, France; French Reference Center for Trophoblastic Disease, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre Bénite, France.
Mod Pathol. 2023 Jan;36(1):100046. doi: 10.1016/j.modpat.2022.100046.
Gestational trophoblastic diseases derived from the chorionic-type intermediate trophoblast include benign placental site nodule (PSN) and malignant epithelioid trophoblastic tumor (ETT). Among PSNs, the World Health Organization classification introduced a new entity named atypical placental site nodule (APSN), corresponding to an ETT precursor, for which diagnostic criteria remain unclear, leading to a risk of overdiagnosis and difficulties in patient management. We retrospectively studied 8 PSNs, 7 APSNs, and 8 ETTs to better characterize this new entity and performed immunohistochemical analysis (p63, human placental lactogen, Cyclin E, and Ki67), transcriptional analysis using the NanoString method to quantify the expression of 760 genes involved in the main tumorigenesis pathways, and RNA sequencing to identify fusion transcripts. The immunohistochemical analysis did not reveal any significant difference in Cyclin E expression among the 3 groups (P = .476), whereas the Ki67 index was significantly (P < .001) higher in ETT samples than in APSN and PSN samples. None of the APSN samples harbored the LPCAT1::TERT fusion transcripts, in contrast to 1 of 6 ETT samples, as previously described in 2 of 3 ETT samples. The transcriptomic analysis allowed robust clustering of ETTs distinct from the APSN/PSN group but failed to differentiate APSNs from PSNs. Indeed, only 7 genes were differentially expressed between PSN and APSN samples; CCL19 upregulation and EPCAM downregulation were the most distinguishing features of APSNs. In contrast, 80 genes differentiated ETTs from APSNs, establishing a molecular signature for ETT. Gene set analysis identified significant enrichments in the DNA damage repair, immortality and stemness, and cell cycle signaling pathways when comparing ETTs and APSNs. These results suggested that APSN might not represent a distinct entity but rather a transitional stage between PSN and ETT. RNA sequencing and the transcriptional signature of ETT described herein could serve as triage for APSN from curettage or biopsy material, enabling the identification of cases that need further clinical investigations.
来源于绒毛膜型中间滋养层的妊娠滋养细胞肿瘤包括良性胎盘部位结节（PSN）和恶性上皮样滋养细胞肿瘤（ETT）。在 PSN 中，世界卫生组织分类引入了一个新实体，命名为不典型胎盘部位结节（APSN），对应于 ETT 的前体，其诊断标准仍不清楚，导致过度诊断的风险和患者管理的困难。我们回顾性研究了 8 例 PSN、7 例 APSN 和 8 例 ETT，以更好地描述这一新实体，并进行免疫组织化学分析（p63、人胎盘催乳素、细胞周期蛋白 E 和 Ki67）、使用 NanoString 方法进行转录分析以定量评估 760 个参与主要肿瘤发生途径的基因的表达，并进行 RNA 测序以鉴定融合转录本。免疫组织化学分析显示，3 组之间 Cyclin E 的表达无显著差异（P=.476），而 ETT 样本中的 Ki67 指数明显高于 APSN 和 PSN 样本（P<.001）。与先前在 3 例 ETT 样本中的 2 例中描述的情况相反，没有一个 APSN 样本携带 LPCAT1::TERT 融合转录本，而在 6 例 ETT 样本中的 1 例中存在该融合转录本。转录组分析能够将 ETT 与 APSN/PSN 组进行稳健聚类，但无法区分 APSN 和 PSN。事实上，PSN 和 APSN 样本之间仅有 7 个基因表达差异；CCL19 的上调和 EPCAM 的下调是 APSN 的最显著特征。相反，80 个基因将 ETT 与 APSN 区分开来，为 ETT 建立了一个分子特征。当比较 ETT 和 APSN 时，基因集分析鉴定出 DNA 损伤修复、永生和干细胞特性以及细胞周期信号通路的显著富集。这些结果表明，APSN 可能不是一个独立的实体，而是 PSN 和 ETT 之间的过渡阶段。本文中描述的 ETT 的 RNA 测序和转录特征可作为 APSN 从刮宫或活检材料中进行分类的手段，有助于识别需要进一步临床研究的病例。
