Garces Sofia, Medeiros L Jeffrey, Marques-Piubelli Mario Luiz, Coelho Siqueira Sheila Aparecida, Miranda Roberto N, Cuglievan Branko, Sriganeshan Vathany, Medina Ana Maria, Garces Juan Carlos, Saluja Karan, Bhattacharjee Meenakshi B, Khoury Joseph D, Li Shaoying, Xu Jie, Jelloul Fatima Zahra, Thakral Beenu, Cameron Yin C
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Hum Pathol. 2022 Mar;121:36-45. doi: 10.1016/j.humpath.2021.12.013. Epub 2022 Jan 4.
Activating mutations in the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway have been shown in nearly half of the cases of Rosai-Dorfman disease (RDD). Cyclin D1, a key cell cycle regulator, constitutes a major downstream target of the MAPK/ERK pathway. In this study, we aim to further understand the pathogenesis of RDD by assessing the lesional histiocytes for cyclin D1, p-ERK, Ki-67, and BCL-2 by immunohistochemistry. We assessed 35 samples of RDD and a control group of histiocyte-rich reactive lesions. Cyclin D1 was expressed in about 90% of cases of RDD. Cyclin D1 was positive in 25-95% (median, 85%) of lesional histiocytes, was moderately/strongly expressed in 97% of cyclin D1-positive cases, and was significantly higher than in control specimens. p-ERK was positive in 16 of 30 (53%) cases of RDD and was negative in all controls. All p-ERK-positive RDD cases had concurrent cyclin D1 expression, whereas more than a third of cyclin D1-positive cases were negative for p-ERK. Ki-67 was low in RDD (median, 3%). BCL-2 was positive in lesional histiocytes in nine of 10 RDD cases assessed. Overall, these findings point to unexpected, potential roles of these molecules in the pathogenesis of RDD. Overexpression of cyclin D1 in the absence of ERK phosphorylation in a subset of RDD cases opens the possibility of oncogenic mechanisms bypassing ERK and supports the notion that cyclin D1 overexpression in RDD is multifactorial. Moreover, the observed lack of correlation between cyclin D1 with Ki-67 proliferative index suggests that prosurvival actions of cyclin D1 are, at least in part, cell cycle independent. Finally, expression of BCL-2 and the low Ki-67 index suggest that RDD might be driven by antiapoptotic rather than proproliferative oncogenic mechanisms.
在近一半的窦组织细胞增生症伴巨大淋巴结病（Rosai-Dorfman disease，RDD）病例中，已发现丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）途径存在激活突变。细胞周期蛋白D1是一种关键的细胞周期调节因子，是MAPK/ERK途径的主要下游靶点。在本研究中，我们旨在通过免疫组织化学评估病变组织细胞中的细胞周期蛋白D1、磷酸化ERK（p-ERK）、Ki-67和BCL-2，以进一步了解RDD的发病机制。我们评估了35例RDD样本以及一组富含组织细胞的反应性病变作为对照。细胞周期蛋白D1在约90%的RDD病例中表达。细胞周期蛋白D1在25%-95%（中位数为85%）的病变组织细胞中呈阳性，在97%的细胞周期蛋白D1阳性病例中呈中度/强表达，且显著高于对照样本。p-ERK在30例RDD病例中的16例（53%）呈阳性，在所有对照中均为阴性。所有p-ERK阳性的RDD病例均同时有细胞周期蛋白D1表达，而超过三分之一的细胞周期蛋白D1阳性病例p-ERK为阴性。RDD中Ki-67水平较低（中位数为3%）。在评估的10例RDD病例中，有9例病变组织细胞中BCL-2呈阳性。总体而言，这些发现表明这些分子在RDD发病机制中具有意想不到的潜在作用。在一部分RDD病例中，细胞周期蛋白D1在没有ERK磷酸化的情况下过度表达，这为绕过ERK的致癌机制提供了可能性，并支持RDD中细胞周期蛋白D1过度表达是多因素的这一观点。此外，观察到细胞周期蛋白D1与Ki-67增殖指数之间缺乏相关性，这表明细胞周期蛋白D1的促生存作用至少部分与细胞周期无关。最后，BCL-2的表达以及低Ki-67指数表明，RDD可能由抗凋亡而非促增殖致癌机制驱动。
