Asano Ryoko, Asai-Sato Mikiko, Miyagi Yohei, Mizushima Taichi, Koyama-Sato Makiko, Nagashima Yoji, Taguri Masataka, Sakakibara Hideya, Hirahara Fumiki, Miyagi Etsuko
Department of Obstetrics, Gynecology, and Molecular Reproductive Science, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
Department of Obstetrics, Gynecology, and Molecular Reproductive Science, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
Am J Obstet Gynecol. 2015 Aug;213(2):199.e1-8. doi: 10.1016/j.ajog.2015.02.016. Epub 2015 Feb 25.
Myomatous erythrocytosis syndrome is a rare complication of uterine leiomyoma caused by erythropoietin (EPO) that is produced by tumor cells. We assessed the EPO expression in leiomyomas and investigated the effects of EPO on the tumor growth.
Tissue samples were collected from 114 patients with uterine leiomyomas who underwent myomectomy or hysterectomy in Yokohama City University Hospital. From 17 patients, the corresponding normal myometrium was also collected. All samples were analyzed for EPO messenger RNA (mRNA) expression by real-time reverse transcription-polymerase chain reaction. EPO protein expression was determined by an enzyme-linked immunosorbent assay. The relationships between EPO expression and clinicopathological features were retrospectively analyzed using the patients' charts. Blood vessel density and maturity were assessed using hematoxylin-eosin staining and CD34 immunohistochemistry.
EPO mRNA expression was detected in 108 of 114, or 95%, of the leiomyomas. The mean EPO mRNA expression in the leiomyoma was higher than the corresponding normal myometrium (3836 ± 4122 vs 1455 ± 2141; P = .025 by Wilcoxon rank test). The EPO mRNA expression in the leiomyomas varied extensively among samples, ranging from undetectable levels to 18-fold above the mean EPO mRNA of normal myometrium. EPO protein production was observed concomitant with mRNA expression. A positive correlation of leiomyoma size and EPO mRNA expression was shown by Spearman rank correlation coefficient (ρ = 0.294; P = .001), suggesting the involvement of EPO in leiomyoma growth. The blood vessel maturity was also significantly increased in EPO-producing leiomyomas (high vessel maturity in high vs low EPO group: 67% vs 20%; P = .013 by Fisher exact test).
This report demonstrates that EPO is produced in most of conventional leiomyomas and supports a model in which EPO accelerates tumor growth, possibly by inducing vessel maturity. Our study suggests one possible mechanism by which some uterine leiomyomas reach a large size, and the understanding of EPO expression patterns in these tumors may be useful for management of the patients with leiomyomas.
肌瘤性红细胞增多症综合征是由肿瘤细胞产生的促红细胞生成素（EPO）引起的子宫平滑肌瘤罕见并发症。我们评估了平滑肌瘤中EPO的表达，并研究了EPO对肿瘤生长的影响。
收集了在横滨市立大学医院接受肌瘤切除术或子宫切除术的114例子宫平滑肌瘤患者的组织样本。从17例患者中，还收集了相应的正常子宫肌层。通过实时逆转录-聚合酶链反应分析所有样本的EPO信使核糖核酸（mRNA）表达。通过酶联免疫吸附测定法测定EPO蛋白表达。使用患者病历回顾性分析EPO表达与临床病理特征之间的关系。使用苏木精-伊红染色和CD34免疫组织化学评估血管密度和成熟度。
114例平滑肌瘤中有108例（95%）检测到EPO mRNA表达。平滑肌瘤中EPO mRNA的平均表达高于相应的正常子宫肌层（3836±4122对1455±2141；Wilcoxon秩和检验P = 0.025）。平滑肌瘤中EPO mRNA的表达在样本间差异很大，从检测不到的水平到高于正常子宫肌层平均EPO mRNA的18倍。观察到EPO蛋白产生与mRNA表达相伴。Spearman秩相关系数显示平滑肌瘤大小与EPO mRNA表达呈正相关（ρ = 0.294；P = 0.001），提示EPO参与平滑肌瘤生长。产生EPO的平滑肌瘤中血管成熟度也显著增加（高EPO组与低EPO组高血管成熟度：67%对20%；Fisher确切概率检验P = 0.013）。
本报告表明大多数传统平滑肌瘤产生EPO，并支持EPO可能通过诱导血管成熟加速肿瘤生长的模型。我们的研究提示了一些子宫平滑肌瘤长到较大尺寸的一种可能机制，了解这些肿瘤中EPO的表达模式可能有助于平滑肌瘤患者的管理。
